CN108690862A

CN108690862A - Medicament sifting motion system and method

Info

Publication number: CN108690862A
Application number: CN201710231144.1A
Authority: CN
Inventors: 张超; 井多辉
Original assignee: Hangzhou Hema Biological Technology Co Ltd
Current assignee: Hemachao Biotechnology Shanghai Co ltd
Priority date: 2017-04-10
Filing date: 2017-04-10
Publication date: 2018-10-23

Abstract

This application involves a kind of method and systems for screening leukemia treating drug candidate.The method includes:1) in the first screening group the entry evaluation drug candidate validity;And 2) directly recommend the drug candidate to enter clinical test as a result, determining according to the entry evaluation, or the validity of the drug candidate is further assessed in all or part of member of the second screening group.The present processes and system significantly improve the success rate of clinical test.

Description

Medicament sifting motion system and method

Technical field

This application involves a kind of method and systems for screening leukemia treating drug candidate.Particularly, the method Can be used for carrying out preclinical screening to the drug candidate of leukemia treating with system, to greatly improve clinical test efficiency and Success rate.

Background technology

Although there is numerous new drugs for treating leukaemia to be designed to research and develop and achieve in vitro experiment well every year Experimental result, but 90% or more new drug in clinical test fail.Simultaneously as clinical resources are limited, it is annual to only have Nearly 20 kinds of new drugs have an opportunity to enter clinical experimental stage.Therefore, there is an urgent need for effective method and systems to carry out preclinical screening, from And suitable drug candidate is selected to carry out clinical test, and improve the efficiency and success rate of clinical test.

Invention content

This application provides a kind of method and systems for screening leukemia treating drug candidate.Particularly, the side Method and system can be used for carrying out preclinical screening to the drug candidate of leukemia treating, to greatly improve the efficiency of clinical test And success rate.

In one aspect, this application provides a kind of method for carrying out Preclinical evaluation to drug candidate, the sides Method includes:1) in the first screening group the entry evaluation drug candidate validity;And 2) according to the knot of the entry evaluation Fruit determines and directly recommends the drug candidate into clinical test, or into one in all or part of member of the second screening group Step assesses the validity of the drug candidate;The wherein described first screening group and the second screening group include respectively at least one white blood Transplantable tumor (PDX) mouse model in patient source, the transplantable tumor of each mouse model represent a kind of leukaemia hypotype;Institute It is humanized mouse model to state mouse model;And the leukaemia in the second screening group representated by the transplantable tumor of mouse model Hypotype includes the leukaemia hypotype representated by the transplantable tumor of mouse model in all first screening groups.

In the certain embodiments of the method, the transplantable tumor of each mouse model is originated from the first screening group Leukaemic is different from the leukaemic that the transplantable tumor of each mouse model in the second screening group is originated from.

In the certain embodiments of the method, the leukaemic is the leukaemic for showing drug resistance And/or the leukaemic of recurrence.

In the certain embodiments of the method, the leukaemia includes acute lymphoblastic leukemia, such as described Leukaemia may include one or more hypotypes of acute lymphatic leukemia.

It is white representated by the transplantable tumor of mouse model in the first screening group in the certain embodiments of the method Blood disease hypotype includes selected from the group below one or more:B cell precursor cell Acute Lymphoblastic Leukemia (BCP-ALL), T are thin Born of the same parents' acute lymphoblastic leukemia (T-ALL) and mixed lineage leukemia (MLL).

In the certain embodiments of the method, the transplantable tumor of mouse model has following thin in the first screening group It is one or more in born of the same parents' genetics characteristics:Normally;Ph+,t(9;22);t(17;19);[4]/46,XY[14];t(11;19) and t(4;11).

In the certain embodiments of the method, the first screening group include at least 50% have represent leukaemia The different mouse models of the transplantable tumor of hypotype BCP-ALL.

In the certain embodiments of the method, has described at least 50% and represent leukaemia hypotype BCP-ALL's In the different mouse models of transplantable tumor, at least 30% transplantable tumor has normal Cytogenetic Features.

In the certain embodiments of the method, has described at least 50% and represent leukaemia hypotype BCP-ALL's In the different mouse models of transplantable tumor, at least 10% transplantable tumor has Cytogenetic Features Ph+, t (9;22).

In the certain embodiments of the method, has described at least 50% and represent leukaemia hypotype BCP-ALL's In the different mouse models of transplantable tumor, at least 10% transplantable tumor has Cytogenetic Features t (17;19).

In the certain embodiments of the method, the first screening group include at least 30% have represent leukaemia The different mouse models of the transplantable tumor of hypotype T-ALL.

In the certain embodiments of the method, there is the shifting for representing leukaemia hypotype T-ALL described at least 30% In the different mouse models for planting tumor, at least 10% transplantable tumor has normal Cytogenetic Features.

In the certain embodiments of the method, there is the shifting for representing leukaemia hypotype T-ALL described at least 30% In the different mouse models for planting tumor, at least 10% transplantable tumor has Xi Baoyichuanxuetezheng [4]/46,XY[14].

In the certain embodiments of the method, the first screening group include at least 20% have represent leukaemia The different mouse models of the transplantable tumor of hypotype MLL.

In the certain embodiments of the method, there is the transplanting for representing leukaemia hypotype MLL described at least 20% In the different mouse models of tumor, at least 10% transplantable tumor has Cytogenetic Features t (11;19).

In the certain embodiments of the method, there is the transplanting for representing leukaemia hypotype MLL described at least 20% In the different mouse models of tumor, at least 10% transplantable tumor has Cytogenetic Features t (4;11).

In the certain embodiments of the method, representated by the transplantable tumor for mouse model in the first screening group Each leukaemia hypotype, include two or more with the transplantable tumor for representing the hypotype in the second screening group Mouse model.

It is white representated by the transplantable tumor of mouse model in the second screening group in the certain embodiments of the method Blood disease hypotype includes selected from the group below one or more:BCP-ALL, T-ALL, MLL and Pre-Tcell precursor acute lymphoblastic Chronic myeloid leukemia (ETP-ALL).

In the certain embodiments of the method, the transplantable tumor of mouse model has following thin in the second screening group It is one or more in born of the same parents' genetics characteristics or genetics characteristics:Normally;t(1;11);Ph+,t(9;22);t(17;19);[4]/ 46,XY[14];t(11;19);t(4;11) it is mutated with JAK.

In the certain embodiments of the method, the second screening group include it is at least ten kinds of have represent leukaemia The different mouse models of the transplantable tumor of hypotype BCP-ALL.

In the certain embodiments of the method, the second screening group include it is at least ten kinds of have represent leukaemia The different mouse models of the transplantable tumor of hypotype T-ALL.

In the certain embodiments of the method, the second screening group include it is at least seven kinds of have represent leukaemia The different mouse models of the transplantable tumor of hypotype MLL.

In the certain embodiments of the method, the second screening group include it is at least six kinds of have represent leukaemia The different mouse models of the transplantable tumor of hypotype ETP-ALL.

In the certain embodiments of the method, the second screening group includes at least ten kinds of with prominent comprising JAK The different mouse models of the transplantable tumor of change.

In the certain embodiments of the method, in the second screening group, the transplanting of at least one mouse model Tumor is mutated comprising JAK, and the transplantable tumor represents BCP-ALL hypotypes.

In the certain embodiments of the method, in the second screening group, the transplanting of at least one mouse model Tumor has normal Cytogenetic Features, and the transplantable tumor represents BCP-ALL hypotypes or T-ALL hypotypes.

In the certain embodiments of the method, in the second screening group, the transplanting of at least one mouse model Tumor has Cytogenetic Features Ph+, t (9;22), and the transplantable tumor represents BCP-ALL hypotypes.

In the certain embodiments of the method, in the second screening group, the transplanting of at least one mouse model Tumor has Cytogenetic Features t (1;11), and the transplantable tumor represents BCP-ALL, T-ALL or MLL hypotype.

In the certain embodiments of the method, in the second screening group, the transplanting of at least one mouse model Tumor has Cytogenetic Features t (17;19), and the transplantable tumor represents BCP-ALL hypotypes.

In the certain embodiments of the method, in the second screening group, the transplanting of at least one mouse model Tumor has Xi Baoyichuanxuetezheng [4]/46,XY[14], and the transplantable tumor represents T-ALL hypotypes.

In the certain embodiments of the method, in the second screening group, the transplanting of at least one mouse model Tumor has Cytogenetic Features t (11;19), and the transplantable tumor represents BCP-ALL, T-ALL or MLL hypotype.

In the certain embodiments of the method, in the second screening group, the transplanting of at least one mouse model Tumor has Cytogenetic Features t (4;11), and the transplantable tumor represents BCP-ALL, T-ALL or MLL hypotype.

In the certain embodiments of the method, the validity of the entry evaluation drug candidate includes:To described All transplantable tumor mouse models in one screening group apply suitable drug candidate respectively, and monitor leukaemia cell each Ratio in the transplantable tumor mouse model peripheral blood cells judges institute when the ratio is maintained below about 1% at least about 2 weeks It is effective to state drug candidate.

In the certain embodiments of the method, in the entry evaluation in the first screening group at least 80% transplantable tumor mouse model shows effective drug candidate, is determined as 1) directly recommending to enter clinical test;Or 2) The validity of the drug candidate is further assessed in all or part of member of the second screening group.

In the certain embodiments of the method, in the entry evaluation in the first screening group 80% Transplantable tumor mouse model below shows effective drug candidate, into one in all or part of member of the second screening group Step assesses the validity of the drug candidate.

In the certain embodiments of the method, in the first screening group 80% or less in the entry evaluation Transplantable tumor mouse model show that the effective drug candidate is the targeted drug for specific target spot, and the method packet It includes:It selects to be positive transplantable tumor mouse model to the specific target spot from the second screening group, and in selected shifting Plant the validity that the drug candidate is further assessed in tumor mouse model.

In the certain embodiments of the method, the drug candidate is in the entry evaluation to first screening 50% or more and 80% transplantable tumor mouse model below is shown effectively in group, and the drug candidate is in the first screening group In be more than 80% the specific leukaemia hypotype of representative transplantable tumor mouse model in effectively, and the method includes:In the second sieve Select the validity that the drug candidate is further assessed in the transplantable tumor mouse model for representing the specific leukaemia hypotype in group.

In the certain embodiments of the method, the drug candidate is selected from kinases inhibitor, Apoptosis tune Agent is saved, gene splitting drug, cell division inhibitor, MDM2 class oncogene inhibitor, antibody class drug and/or other changes are promoted Treat pharmaceutical addition agent.

In the certain embodiments of the method, the drug candidate may also include one or more in the following group:It is long Spring new alkali, dexamethasone, cyclophosphamide, vincristine, dexamethasone and leunase combination, NSC750854, topology For health, Volasertib, Serdemetan, JNJ-26481585 and KTP-330.

In the certain embodiments of the method, the kinases inhibitor includes AZD8055, MLN0128, GSK690693, MK-2206, SAR245408, rapamycin, MLN0128, selumetinib, AZD6244, PCI-32765, Ibrutinib, SGI-1776, dinaciclib, VS-4718, temsirolimus, sorafenib, sunitinib, Ruxolitinib, AZD1480 and/or dasatinib.

In the certain embodiments of the method, the apoptosis regulators include ABT-263 (navitoclax), ABT-199 (venetoclax), LCL161 and/or birinapant.

In the certain embodiments of the method, the MDM2 classes oncogene inhibitor includes MK-8242 (SCH And/or RG7112 900242).

In the certain embodiments of the method, the rush gene splitting drug includes PR-104, cytarabine (CPX-351), daunorubicin (Vyxeos), topotecan, clofarabine and/or temozolomide.

In the certain embodiments of the method, the cell division inhibitor includes eribulin, ispinesib, Bortezomib, carfilzomib and/or alisertib.

In the certain embodiments of the method, the antibody class drug includes SAR3419, blinatumomab, and/ Or inotuzumab.

In the certain embodiments of the method, other described chemotherapeutics additives include alvespimycin, AT13387, PF-03084014, RO-4929097, MLN4924, PG11047, CX-5461, BMN-673, selinexor, Curaxin and/or CBL0137.

On the other hand, this application provides a kind of system for assessing leukemia treating drug candidate, the system packets The first screening group and the second screening group are included, wherein:The first screening group and the second screening group include respectively at least one white The transplantable tumor of the transplantable tumor mouse model in blood patient source, each mouse model represents a kind of leukaemia hypotype;It is described Mouse model is humanized mouse model;And the leukaemia in the second screening group representated by the transplantable tumor of mouse model is sub- Type includes the leukaemia hypotype representated by the transplantable tumor of mouse model in all first screening groups.

In the certain embodiments of the system, the transplantable tumor of each mouse model is originated from the first screening group Leukaemic is different from the leukaemic that the transplantable tumor of each mouse model in the second screening group is originated from.

In the certain embodiments of the system, the leukaemic is the leukaemic for showing drug resistance And/or the leukaemic of recurrence.

In the certain embodiments of the system, the leukaemia includes acute lymphoblastic leukemia, such as described Leukaemia may include one or more hypotypes of acute lymphatic leukemia.

It is white representated by the transplantable tumor of mouse model in the first screening group in the certain embodiments of the system Blood disease hypotype includes selected from the group below one or more:B cell precursor cell Acute Lymphoblastic Leukemia (BCP-ALL), T are thin Born of the same parents' acute lymphoblastic leukemia (T-ALL) and mixed lineage leukemia (MLL).

In the certain embodiments of the system, the transplantable tumor of mouse model has following thin in the first screening group It is one or more in born of the same parents' genetics characteristics:Normally;Ph+,t(9;22);t(17;19);[4]/46,XY[14];t(11;19) and t(4;11).

In the certain embodiments of the system, the first screening group include at least 50% have represent leukaemia The different mouse models of the transplantable tumor of hypotype BCP-ALL.

In the certain embodiments of the system, has described at least 50% and represent leukaemia hypotype BCP-ALL's In the different mouse models of transplantable tumor, at least 30% transplantable tumor has normal Cytogenetic Features.

In the certain embodiments of the system, has described at least 50% and represent leukaemia hypotype BCP-ALL's In the different mouse models of transplantable tumor, at least 10% transplantable tumor has Cytogenetic Features Ph+, t (9;22).

In the certain embodiments of the system, has described at least 50% and represent leukaemia hypotype BCP-ALL's In the different mouse models of transplantable tumor, at least 10% transplantable tumor has Cytogenetic Features t (17;19).

In the certain embodiments of the system, the first screening group include at least 30% have represent leukaemia The different mouse models of the transplantable tumor of hypotype T-ALL.

In the certain embodiments of the system, there is the shifting for representing leukaemia hypotype T-ALL described at least 30% In the different mouse models for planting tumor, at least 10% transplantable tumor has normal Cytogenetic Features.

In the certain embodiments of the system, there is the shifting for representing leukaemia hypotype T-ALL described at least 30% In the different mouse models for planting tumor, at least 10% transplantable tumor has Xi Baoyichuanxuetezheng [4]/46,XY[14].

In the certain embodiments of the system, the first screening group include at least 20% have represent leukaemia The different mouse models of the transplantable tumor of hypotype MLL.

In the certain embodiments of the system, there is the transplanting for representing leukaemia hypotype MLL described at least 20% In the different mouse models of tumor, at least 10% transplantable tumor has Cytogenetic Features t (11;19).

In the certain embodiments of the system, there is the transplanting for representing leukaemia hypotype MLL described at least 20% In the different mouse models of tumor, at least 10% transplantable tumor has Cytogenetic Features t (4;11).

In the certain embodiments of the system, representated by the transplantable tumor for mouse model in the first screening group Each leukaemia hypotype, include two or more with the transplantable tumor for representing the hypotype in the second screening group Mouse model.

It is white representated by the transplantable tumor of mouse model in the second screening group in the certain embodiments of the system Blood disease hypotype includes selected from the group below one or more:BCP-ALL, T-ALL, MLL and Pre-Tcell precursor acute lymphoblastic Chronic myeloid leukemia (ETP-ALL).

In the certain embodiments of the system, the transplantable tumor of mouse model has following thin in the second screening group It is one or more in born of the same parents' genetics characteristics or genetics characteristics:Normally;t(1;11);Ph+,t(9;22);t(17;19);[4]/ 46,XY[14];t(11;19);t(4;11) it is mutated with JAK.

In the certain embodiments of the system, the second screening group include it is at least ten kinds of have represent leukaemia The different mouse models of the transplantable tumor of hypotype BCP-ALL.

In the certain embodiments of the system, the second screening group include it is at least ten kinds of have represent leukaemia The different mouse models of the transplantable tumor of hypotype T-ALL.

In the certain embodiments of the system, the second screening group include it is at least seven kinds of have represent leukaemia The different mouse models of the transplantable tumor of hypotype MLL.

In the certain embodiments of the system, the second screening group include it is at least six kinds of have represent leukaemia The different mouse models of the transplantable tumor of hypotype ETP-ALL.

In the certain embodiments of the system, the second screening group includes at least ten kinds of with prominent comprising JAK The different mouse models of the transplantable tumor of change.

In the certain embodiments of the system, in the second screening group, the transplanting of at least one mouse model Tumor is mutated comprising JAK, and the transplantable tumor represents BCP-ALL hypotypes.

In the certain embodiments of the system, in the second screening group, the transplanting of at least one mouse model Tumor has normal Cytogenetic Features, and the transplantable tumor represents BCP-ALL hypotypes or T-ALL hypotypes.

In the certain embodiments of the system, in the second screening group, the transplanting of at least one mouse model Tumor has Cytogenetic Features Ph+, t (9;22), and the transplantable tumor represents BCP-ALL hypotypes.

In the certain embodiments of the system, in the second screening group, the transplanting of at least one mouse model Tumor has Cytogenetic Features t (17;19), and the transplantable tumor represents BCP-ALL hypotypes.

In the certain embodiments of the system, in the second screening group, the transplanting of at least one mouse model Tumor has Xi Baoyichuanxuetezheng [4]/46,XY[14], and the transplantable tumor represents T-ALL hypotypes.

In the certain embodiments of the system, in the second screening group, the transplanting of at least one mouse model Tumor has Cytogenetic Features t (1;11), and the transplantable tumor represents BCP-ALL, T-ALL or MLL hypotype.

In the certain embodiments of the system, in the second screening group, the transplanting of at least one mouse model Tumor has Cytogenetic Features t (11;19), and the transplantable tumor represents BCP-ALL, T-ALL or MLL hypotype.

In the certain embodiments of the system, in the second screening group, the transplanting of at least one mouse model Tumor has Cytogenetic Features t (4;11), and the transplantable tumor represents BCP-ALL, T-ALL or MLL hypotype.

On the other hand, this application provides the system involved by the disclosure be used to prepare to drug candidate carry out it is preclinical Purposes in the system of assessment.

Those skilled in the art can from detailed description below in easily have insight into the other aspects of the disclosure and excellent Gesture.The illustrative embodiments of the disclosure only have been shown and described in detailed description below.As those skilled in the art will recognize Know, content of this disclosure enables those skilled in the art to be modified without de- disclosed specific implementation mode From the spirit and scope invented involved by the application.Correspondingly, the description in the drawing and description of the application is only example Property, rather than be restrictive.

Description of the drawings

The specific features of invention involved by the application are as shown in the appended claims.By reference in more detail below The illustrative embodiments and attached drawing of description better understood when the application involved the characteristics of inventing and advantage.To attached drawing letter Want specification as follows:

Fig. 1 shows the example schematic diagram of herein described medicament sifting motion system.

Fig. 2 shows the example schematic diagram that drug candidate assessment middle grade divides.

Fig. 3 shows the schematic diagram of assessment result in drug candidate screening.

Fig. 4 shows the assessment result schematic diagram of drug candidate PR-104.

Fig. 5 is shown as the assessment result schematic diagram of drug candidate AZD1480.

Specific implementation mode

Below by specific specific implementation mode illustrate this application involves invention, those skilled in the art can be by this theory Bright book disclosure of that is easily realized by other advantages and effect of the present application.

In this application, term " humanization " usually instigate non-human organism or its tissue, cell, gene expression product, Gene etc. carries human gene, gene expression product, cell and/or tissue.

In this application, term " disease model " is often referred to the individual with disease analog representation, and the individual can be Such as animal, plant, microorganism etc..In some embodiments, the disease model is by animal (for example, mouse, rat etc.) It is formed, for example, the disease model can be formed by mouse, the disease model of acquisition can be mouse model.

In this application, term " leukaemia (Leukemia) " is often referred to because leukaemia cell is largely proliferated, accumulates and is drawn The disease risen, usually starts in marrow.

In this application, term " patient " is often referred to the individual with certain disease characterization, and the disease characterization can refer to The symptom of disease can also refer to the harmful physiological status that cannot be changed in preventing implementations.The individual may include hero Property and/or female, generally comprise people or non-human animal, including but not limited to people, dog, cat, horse, sheep, goat, pig, ox, rabbit, Rat, mouse, monkey etc..In some embodiments, the patient is human patients.

In this application, term " transplantable tumor mouse model " is often referred to the cell by external source (for example, it may be people source is thin Born of the same parents, for another example can be tumour cell, such as leukaemia cell) it is transplanted in Mice Body to build the animal model of acquisition.

In this application, term " leukaemia hypotype " is often referred to according to certain standard to variety classes leukaemia into traveling Group obtained by one step parting, for example, leukaemia usually may include that acute leukemia and chronic leukemia, acute leukemia can wrap Acute lymphoblastic leukemia is included, it is thin to may further include B cell precursor cell acute lymphoid according to immunophenotype difference Born of the same parents' leukaemia, T cell acute lymphoblastic leukemia, mixed lineage leukemia, Pre-Tcell acute lymphoblastic leukemia etc. Hypotype.

In this application, term " drug resistance " is often referred to tested target (for example, pathogen, tumour cell etc.) to medicine The phenomenon that object sensibility reduces, for example, it may be medicine controls tested target (for example, pathogen, tumour cell etc.) Therapeutic effect disappears or reduces.

In this application, term " recurrence " be often referred to patient disease characterization be eliminated or mitigate after, disease characterization once again The phenomenon that occurring or aggravating.

In this application, term " acute lymphoblastic leukemia (acute lymphoblastic leukemia, ALL) " It is often referred to the hematologic malignancies caused by internal lymphocyte abnormality proliferation.

In this application, term " B cell precursor cell Acute Lymphoblastic Leukemia (Precursor B-cell Lymphoblastic leukemia, BCP-ALL) " it is often referred in blood and/or marrow containing excessive B cell lymph mother carefully A kind of acute lymphoblastic leukemia of born of the same parents' (immature white blood cell).

In this application, term " T cell acute lymphoblastic leukemia (T-ALL) " be often referred to blood and/or marrow and/ Or one kind containing excessive T cell lymphoblast (immature white blood cell) is acute in tissue (for example, vertical phrenic lymph nodes) Lymphocytic leukemia.

In this application, term " mixed lineage leukemia (Mixed Lineage Leukemia, MLL) " be often referred to due to No. 11 2 areas 3 of chromosome long arm form a kind of acute lymphoblastic leukemia of MLL fusion proteins with (11q23) transposition.

In this application, term " transposition (translocation) " is often referred to the change of chromosome segment position.

In this application, term " leukaemia (JAK-Mutated Leukemia) containing JAK mutation " is often referred to adjoint There is a kind of leukaemia of JAK gene mutations.

In this application, term " Pre-Tcell acute lymphoblastic leukemia (Early T-cell precursor- Acute lymphoblastic leukemia, ETP-ALL) " it is often referred to a kind of acute lymphoblastic originating from immediate precursors T cell Chronic myeloid leukemia.

In this application, term " natural kill (NK) cell lymphocytic leukemia " is often referred to be increased by NK cell systems A kind of lymphocytic leukemia caused by growing.

In this application, term " leukaemia cell " typically refers to the jejune white of candidate stem cell morbid state differentiation generation Cell.For example, the function of leukaemia cell's usually not normal cell, can but there is very strong proliferative capacity.

In this application, term " normal Cytogenetic Features " be often referred to cell structure and/or functional character just Often (for example, same or similar with the individual features of the cell or tissue of no pathological manifestations or the patient's condition).For example, cell has normally Chromosome structure and/or functional character.For example, Cytogenetic Features, institute can be obtained by cytogenetics banding technique It states cytogenetics banding technique may include, such as chromosomal G-banding technology (G-banded chromosomes), fluorescent in situ Hybridization technique (fluorescent in situ hybridization, FISH), Comparative genomic hybridization (comparative genomic hybridization, CGH) etc..

In this application, term " Ph+ " (Philadelphia chromosome positive) is often referred to cell (example Such as, leukaemia cell) in No. 22 chromosome a kind of defect, No. 22 chromosome long arms can be shown as and No. 9 chromosomes occur Transposition forms new chromosome, ABL1 (the abelson murine leukemia viral being specifically as follows on No. 9 chromosome Oncogene homolog 1) gene is juxtaposed to the BCR (breakpoint on (juxtaposed onto) No. 22 chromosomes Cluster region) gene, cause gene BCR and ABL to merge.

In this application, term " [t(9;22)]" be often referred to that transposition occurs between No. 9 chromosomes and No. 22 chromosomes.

In this application, term " t (11;19) it " is often referred to that transposition occurs between No. 11 chromosomes and No. 19 chromosomes.

In this application, term " t (4;11) it " is often referred to that transposition occurs between No. 4 chromosomes and No. 11 chromosomes.

In this application, term " t (17;19) it " is often referred to that transposition occurs between No. 17 chromosomes and No. 19 chromosomes.

In this application, term " drug candidate " be often referred to some may be as the substance that drug uses, these substances can To be assessed by method appropriate, to obtain the information of its biological activity, pharmacological action and effect etc..

In this application, term " antibody " is used in its broadest sense in this application, is specifically including but not limited to Monoclonal antibody (including full length monoclonal antibodies), polyclonal antibody, multi-specificity antibody (for example, bispecific antibody) and its Antigen-binding fragment etc..

In this application, term " protein kinase (protein kinases, PK) " be often referred to one kind being capable of catalytic proteins The enzyme of phosphorylation reaction.

In this application, term " kinases inhibitor " is often referred to that the substance of protein kinase activity can be inhibited.

In this application, term " apoptosis regulators " be often referred to regulate and control (for example, it may be accelerate, delay or Inhibit etc.) substance of Apoptosis.

In this application, term " promote gene splitting drug " be often referred to can to promote gene (for example, DNA, That is DNA) decompose substance.

In this application, term " cell division inhibitor " is often referred to postpone or inhibit fissional substance.

In this application, term " MDM2 class oncogene inhibitor " is often referred to reduce or inhibit the table of MDM2 genes Up to horizontal or can reduce or the substance of the activity that inhibits MDM2 etc., the expression of the gene can be the expression of mRNA Horizontal or albumen expression etc..

In this application, term " antibody class drug " be often referred to include at least one antibody drug.

In this application, term " chemotherapeutics additives " is often referred to the drug that can be used cooperatively with chemotherapeutics, this A little drugs usually can improve the therapeutic effect of chemotherapeutics.

In this application, term " about " typically refers to become in the range of specified numerical value above and below 0.5%-10% It is dynamic, for example, specified numerical value above and below 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, it changes in the range of 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5% or 10%.

On the one hand, this application provides a kind of methods for carrying out Preclinical evaluation to drug candidate.This method can wrap Include the validity of the entry evaluation drug candidate in the first screening group.This method may also include the knot according to the entry evaluation Fruit determines and directly recommends the drug candidate into clinical test, or into one in all or part of member of the second screening group Step assesses the validity of the drug candidate.The first screening group and the second screening group can include respectively at least one leukaemia The transplantable tumor mouse model in patient source.The transplantable tumor of each mouse model can represent a kind of leukaemia hypotype.It is described small Mouse model can be humanized mouse model.Leukaemia hypotype in the second screening group representated by the transplantable tumor of mouse model It may include the leukaemia hypotype representated by the transplantable tumor of mouse model in the first screening group, for example, the second screening group Leukaemia hypotype representated by the transplantable tumor of middle mouse model may include the transplanting of mouse model in all first screening groups Leukaemia hypotype representated by tumor.

In the method for the application, the validity of the entry evaluation drug candidate may include to first screening All transplantable tumor mouse models in group apply suitable drug candidate respectively, and monitor leukaemia cell in each shifting Plant the ratio in tumor mouse model peripheral blood cells or ratio variation.

In the method for the application, in the entry evaluation in the first screening group at least 70% (for example, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, At least 95% or more) transplantable tumor mouse model shows effective drug candidate, can be determined as 1) directly recommending to enter Clinical test;Or 2) validity of the drug candidate is further assessed in all or part of member of the second screening group.

In the method for the application, in the entry evaluation in the first screening group 80% or less (for example, 70% hereinafter, 65% hereinafter, 60% hereinafter, 55% hereinafter, 50% hereinafter, 45% hereinafter, or 40%-80%, 45%- 80%, 50%-80%, 55%-80%, 60%-80%, 65%-80%, 70%-80%, 75%-80%) transplantable tumor mouse Model shows effective drug candidate, and candidate's medicine can be further assessed in all or part of member of the second screening group The validity of object.

In some embodiments, in the entry evaluation in the first screening group 80% or less (for example, 70% Hereinafter, 65% hereinafter, 60% hereinafter, 55% hereinafter, 50% hereinafter, 45% hereinafter, or 40%-80%, 45%-80%, 50%- 80%, 55%-80%, 60%-80%, 65%-80%, 70%-80%, 75%-80%) transplantable tumor mouse model show The drug candidate of effect is the targeted drug for specific target spot, and the method includes:It is selected from the second screening group It selects and is the transplantable tumor mouse model of the positive to the specific target spot, and further assessed in selected transplantable tumor mouse model The validity of the drug candidate.For example, as it is known that the drug candidate is the targeted drug for certain specific target spot, then described second May include being right in positive transplantable tumor mouse model or the optional second screening group to the specific target spot in screening group The specific target spot is positive transplantable tumor mouse model (for example, the transplantable tumor of the mouse model is originated from is to the specific target spot Positive leukaemic).In this application, to certain specific target spot be the positive typically refer to the patient, transplantable tumor, tissue, There are the target spot or its related mutations or variant in cell or mouse model.For example, drug candidate Dasatinib (Dasatinib) it is for Ph+[t(9;22)]Targeted drug, then may be selected the second screening group in have include cytogenetics Learn feature Ph+[t(9;22)]The mouse model of transplantable tumor further assess the validity of the drug candidate, can by it is other not With including Cytogenetic Features Ph+[t(9;22)]Transplantable tumor mouse model as a contrast.

In some embodiments, the drug candidate in the entry evaluation in the first screening group 50% with Upper and 80% transplantable tumor mouse model below shows effectively, and the drug candidate in the first screening group more than 80% The specific leukaemia hypotype of representative transplantable tumor mouse model in effectively, and the method includes:It is represented in the second screening group The validity of the drug candidate is further assessed in the transplantable tumor mouse model of the specific leukaemia hypotype.For example, described first In step assessment, certain drug candidate shows 50% or more and 80% transplantable tumor mouse model below in the first screening group Effect, can further assess its effective sex ratio for the transplantable tumor mouse model of each specific subtype.If the drug candidate To be more than in the first screening group 80% the specific leukaemia hypotype of representative (for example, T-ALL hypotypes) transplantable tumor mouse mould Type is effective, then may include the transplantable tumor mouse model for representing the specific leukaemia hypotype in the second screening group or may be selected The transplantable tumor mouse model of the specific leukaemia hypotype is represented in the second screening group (for example, representing leukaemia hypotype T-ALL Transplantable tumor mouse model) further assess the validity of the drug candidate.

It can be by monitoring huCD45 in the transplantable tumor mouse model peripheral blood⁺,huCD19⁺,huCD3⁺, and/or huCD33⁺The ratio or ratio of cell change to monitor growing state of the leukaemia cell from the patient in the Mice Body. For example, when the leukaemia of the patient is B cell type leukaemia, it can be by monitoring in the transplantable tumor mouse model peripheral blood huCD19⁺The ratio or ratio of cell change to monitor growth of the leukaemia cell from the patient in the Mice Body Situation.For example, when the leukaemia of the patient is T cell type leukaemia, it can be by monitoring outside the transplantable tumor mouse model HuCD3 in all blood⁺The ratio or ratio of cell change to monitor the leukaemia cell from the patient in the Mice Body Growing state.

After application drug candidate, huCD45 in the mouse model peripheral blood cells⁺,huCD19⁺,huCD3⁺, and/or huCD33⁺The ratio of cell relative to application the drug candidate before may decrease, be basically unchanged or be increased, Jin Erke The effect of the drug candidate is judged accordingly.In some embodiments, the model periphery can be monitored by flow cytometry HuCD45 in blood⁺,huCD19⁺,huCD3⁺, and/or huCD33⁺The ratio of cell.In some embodiments, when the white blood Sick cell is (for example, huCD45⁺,huCD19⁺,huCD3⁺, and/or huCD33⁺Cell) in the mouse model peripheral blood cells Shared ratio is kept below using the ratio before drug, or keep below about 4%, below about 3%, below about 2%, be below about 1% or be below about 0.5%, and maintain at least about 0.5 week, at least about 1 week, at least about 1.5 weeks, at least about 2 weeks, at least about 2.5 When week, at least about 3 weeks, at least about 3.5 weeks or longer time, it is possible to determine that the drug candidate is effective.In certain embodiments In, when the ratio is maintained below about 1% at least about 2 weeks, judge that the drug candidate is effective.

In the present processes, the drug candidate can be selected from kinases inhibitor, and apoptosis regulators promote base Because decomposing drug, cell division inhibitor, MDM2 class oncogene inhibitor, antibody class drug and/or other chemotherapeutics are attached Add agent.

The drug candidate may also include one or more in the following group:Vincristine, dexamethasone, cyclophosphamide are long Spring new alkali, dexamethasone and leunase combination, NSC750854, topotecan, Volasertib, Serdemetan, JNJ-26481585 and KTP-330.

The kinases inhibitor may include AZD8055, MLN0128, GSK690693, MK-2206, SAR245408, Rapamycin, MLN0128, selumetinib, AZD6244, PCI-32765, ibrutinib, SGI-1776, Dinaciclib, VS-4718, temsirolimus, sorafenib, sunitinib, ruxolitinib, AZD1480 and/or dasatinib。

The apoptosis regulators may include ABT-263 (navitoclax), ABT-199 (venetoclax), LCL161 and/or birinapant.

The MDM2 classes oncogene inhibitor may include MK-8242 (SCH 900242) and/or RG7112.

The rush gene splitting drug may include PR-104, cytarabine (CPX-351), daunorubicin (Vyxeos), topotecan, clofarabine and/or temozolomide.

The cell division inhibitor may include eribulin, ispinesib, bortezomib, carfilzomib and/ Or alisertib.

The antibody class drug may include SAR3419, blinatumomab and/or inotuzumab.

Other described chemotherapeutics additives may include alvespimycin, AT13387, PF-03084014, RO- 4929097, MLN4924, PG11047, CX-5461, BMN-673, selinexor, curaxin and/or CBL0137.

In some embodiments, the drug candidate may include one or more in the following group:Vincristine, ammonia first leaf Acid, adriamycin, left-handed asparagine, topotecan, clofarabine, Carfilzomib, tesirolimus, is replaced up to sand dexamethasone Buddhist nun, bortezomib, SAR3419, all-trans retinoic acid, SAHA, Sutent, cyclophosphamide and retinamide.

For example, in some embodiments, the drug candidate includes vincristine and the vincristine is suitable for (example Such as, with suitable content and dosage form presence) it requires to be applied to the mouse model according to following:It is applied suitable for passing through intraperitoneal injection With each amount of application is 0.5mg/kg, and application is primary weekly and persistently applies 3-6 weeks.In some embodiments, the candidate Drug includes ninopterin, and the ninopterin is suitable for (for example, with suitable content and dosage form presence) and is required according to following It is applied to the mouse model:Suitable for pass through intraperitoneal injection application, each amount of application be 3-6mg/kg, once-a-day administration, every It applies in week and persistently applies 6-10 weeks.In some embodiments, the drug candidate includes dexamethasone, and described fills in rice Pine is suitable for (for example, with suitable content and dosage form presence) and is applied to the mouse model according to following requirement:Suitable for passing through abdomen Chamber injection application, each amount of application be 10-20mg/kg, once-a-day administration and persistently apply 3-6 weeks.In certain embodiments In, the drug candidate includes adriamycin, and the adriamycin is suitable for (for example, with suitable content and dosage form presence) according to such as Lower requirement is applied to the mouse model:Suitable for passing through intravenous injection application, each amount of application is 0.5-3mg/kg, is applied weekly Once and persistently apply 3-6 weeks.In some embodiments, the drug candidate includes left-handed asparagine, and described left-handed Asparagine is suitable for (for example, with suitable content and dosage form presence) and is applied to the mouse model according to following requirement:It is suitable for By be injected intraperitoneally apply, each amount of application be 500-2000KU/kg, once-a-day administration and persistently apply 3-6 weeks.Certain In embodiment, the drug candidate includes topotecan, and the topotecan is described suitable for being applied to according to following requirement Mouse model:Suitable for pass through intraperitoneal injection application, each amount of application be 0.1-5mg/kg, once-a-day administration and persistently apply 2- It 8 weeks, is discontinued one week after two weeks.In some embodiments, the drug candidate includes clofarabine, and the chlorine farad Shore is suitable for being applied to the mouse model according to following requirement:Suitable for passing through intraperitoneal injection application, each amount of application is 10- 100mg/kg, once-a-day administration and persistently apply 3-6 weeks.In some embodiments, the drug candidate includes Ka Feizuo Rice, and the Carfilzomib is suitable for being applied to the mouse model according to following requirement:Suitable for passing through intravenous injection application, every time Amount of application is 0.1-10mg/kg, and application is secondary weekly and persistently applies 3-6 weeks.In some embodiments, the drug candidate Including tesirolimus, and the tesirolimus is suitable for being applied to the mouse model according to following requirement:Suitable for passing through abdomen Chamber injection application, each amount of application be 5-50mg/kg, once-a-day administration and persistently apply 1-3 weeks.In certain embodiments In, the drug candidate includes Dasatinib, and the Dasatinib is suitable for being applied to the mouse model according to following requirement: Suitable for pass through be administered orally, each amount of application be 5-50mg/kg, once-a-day administration and persistently apply 2-6 weeks.In certain implementations In mode, the drug candidate includes bortezomib, and the bortezomib is suitable for being applied to the mouse according to following requirement Model:Suitable for passing through intraperitoneal injection application, each amount of application is 0.1-20mg/kg, and application is secondary weekly and persistently applies 4-8 Week.In some embodiments, the drug candidate includes SAR3419, and the SAR3419 is suitable for requiring to apply according to following In the mouse model:Suitable for passing through intraperitoneal injection application, each amount of application is 0.5-50mg/kg, and application is primary weekly and holds It is continuous to apply 4-8 weeks.In some embodiments, the drug candidate includes all-trans retinoic acid, and the all-trans retinoic acid Suitable for being applied to the mouse model according to following requirement:Suitable for passing through intraperitoneal injection application, each amount of application is 0.5-10mg/ Kg, application is primary weekly and persistently applies 2-6 weeks.In some embodiments, the drug candidate includes SAHA, and described SAHA is suitable for being applied to the mouse model according to following requirement:Suitable for passing through intraperitoneal injection application, each amount of application is 100- 500mg/kg, once-a-day administration and persistently apply 3-6 weeks.In some embodiments, the drug candidate includes that easypro Buddhist nun replaces Buddhist nun, and the Sutent is suitable for being applied to the mouse model according to following requirement:It is administered orally suitable for passing through, applies every time It measures for 10-100mg/kg, once-a-day administration and persistently using 2-6 weeks.In some embodiments, the drug candidate includes Cyclophosphamide, and the cyclophosphamide is suitable for being applied to the mouse model according to following requirement:It is applied suitable for passing through intraperitoneal injection It is 30-300mg/kg with, each amount of application, once-a-day administration and persistently applies 2-6 weeks.In some embodiments, described Drug candidate includes retinamide, and the retinamide is suitable for being applied to the mouse model according to following requirement:It is suitable In by be injected intraperitoneally apply, each amount of application be 20-200mg/kg, once-a-day administration and persistently apply 2-6 weeks.

For other drug candidates, those skilled in the art can need really according to present disclosure according to specific Determine suitable method, dosage and/or time using drug candidate in drug screening process.

On the other hand, this application provides a kind of systems for assessing leukemia treating drug candidate.The system can Including the first screening group and the second screening group.The wherein described first screening group and the second screening group can include respectively at least one The transplantable tumor mouse model in leukaemic source.The transplantable tumor of each mouse model can represent a kind of leukaemia hypotype. The mouse model can be humanized mouse model.White blood in the second screening group representated by the transplantable tumor of mouse model Sick hypotype may include the leukaemia hypotype in the first screening group representated by the transplantable tumor of mouse model (for example, described second Leukaemia hypotype in screening group representated by the transplantable tumor of mouse model may include mouse model in all first screening groups Transplantable tumor representated by leukaemia hypotype).

On the other hand, this application provides systems described herein to be used to prepare comment preclinical to drug candidate progress Purposes in the system estimated.

According to the either side of the application, the transplantable tumor of each mouse model is originated from the first screening group leukaemia Patient may differ from the leukaemic that the transplantable tumor of each mouse model in the second screening group is originated from.

According to the either side of the application, the leukaemic can be show drug resistance leukaemic and/ Or the leukaemic of recurrence.Resist for example, the leukaemic can show to have the combination chemotherapy scheme of standard Pharmacological property.

According to the either side of the application, the leukaemia may include (or can be) acute lymphoblastic leukemia (ALL)。

According to the either side of the application, the leukaemia in the first screening group representated by the transplantable tumor of mouse model is sub- Type may include selected from the group below one or more:B cell precursor cell Acute Lymphoblastic Leukemia (BCP-ALL), T cell are anxious Property lymphocytic leukemia (T-ALL) and mixed lineage leukemia (MLL).

According to the either side of the application, the transplantable tumor of mouse model can have following cell to lose in the first screening group It passes one or more in feature:A) normal;b)Ph+,t(9;22);c)t(17;19);d)[4]/46,XY[14];e)t (11;19);F) (4 t and;11).

According to the either side of the application, may include in the first screening group at least 50% have represent leukaemia hypotype The different mouse models of the transplantable tumor of BCP-ALL.There is the transplantable tumor for representing leukaemia hypotype BCP-ALL described at least 50% Different mouse models in, at least 30% transplantable tumor can have normal Cytogenetic Features.In at least 50% tool In the different mouse models for having the transplantable tumor for representing leukaemia hypotype BCP-ALL, at least 10% transplantable tumor can have cell to lose It passes and learns feature Ph+, t (9;22).In the different mouse that described at least 50% has the transplantable tumor for representing leukaemia hypotype BCP-ALL In model, at least 10% transplantable tumor can have Cytogenetic Features t (17;19).

For example, in some embodiments, the first screening group includes 10 kinds of different mouse models, wherein can wrap Include the different mouse models of at least five kinds of transplantable tumors for having and representing leukaemia hypotype BCP-ALL.Described at least five kinds of with generation In the different mouse models of the transplantable tumor of table leukaemia hypotype BCP-ALL, at least three kinds of transplantable tumors can have normal cell to lose It passes and learns feature.In at least five kinds of different mouse models with the transplantable tumor for representing leukaemia hypotype BCP-ALL, at least 1 The transplantable tumor of kind can have Cytogenetic Features Ph+, t (9;22).It is described it is at least five kinds of have represent leukaemia hypotype BCP- In the different mouse models of the transplantable tumor of ALL, at least one kind of transplantable tumor can have Cytogenetic Features t (17;19).

According to the either side of the application, may include in the first screening group at least 30% have represent leukaemia hypotype The different mouse models of the transplantable tumor of T-ALL.Have described at least 30% and represents the transplantable tumor of leukaemia hypotype T-ALL not With in mouse model, at least 10% transplantable tumor can have normal Cytogenetic Features.There is generation described at least 30% In the different mouse models of the transplantable tumor of table leukaemia hypotype T-ALL, at least 10% transplantable tumor can have cytogenetics special Levy [4]/46,XY[14].

For example, in some embodiments, the first screening group includes 10 kinds of different mouse models, wherein can wrap Include the different mouse models of at least three kinds of transplantable tumors for having and representing leukaemia hypotype T-ALL.Described at least three kinds of with representative In the different mouse models of the transplantable tumor of leukaemia hypotype T-ALL, at least one kind of transplantable tumor can have normal cytogenetics Feature.In at least three kinds of different mouse models with the transplantable tumor for representing leukaemia hypotype T-ALL, at least one kind of shifting Xi Baoyichuanxuetezheng &#91 can be had by planting tumor;4]/46,XY[14].

According to the either side of the application, may include in the first screening group at least 20% have represent leukaemia hypotype The different mouse models of the transplantable tumor of MLL.Have the difference for the transplantable tumor for representing leukaemia hypotype MLL small described at least 20% In mouse model, at least 10% transplantable tumor can have Cytogenetic Features t (11;19).Have described at least 20% and represents In the different mouse models of the transplantable tumor of leukaemia hypotype MLL, at least 10% transplantable tumor can have Cytogenetic Features t (4;11).

For example, in some embodiments, the first screening group includes 10 kinds of different mouse models, wherein can wrap Include the different mouse models of at least two kinds of transplantable tumors for having and representing leukaemia hypotype MLL.Described at least two kinds of white with representing In the different mouse models of the transplantable tumor of blood disease hypotype MLL, at least one kind of transplantable tumor can have Cytogenetic Features t (11; 19).In at least two kinds of different mouse models with the transplantable tumor for representing leukaemia hypotype MLL, at least one kind of transplanting Tumor can have Cytogenetic Features t (4;11).

It is each representated by the transplantable tumor for mouse model in the first screening group according to the either side of the application Leukaemia hypotype is planted, two or more mouse with the transplantable tumor for representing the hypotype are may include in the second screening group Model.

According to the either side of the application, the leukaemia in the second screening group representated by the transplantable tumor of mouse model is sub- Type may include selected from the group below one or more:BCP-ALL, T-ALL, MLL and Pre-Tcell precursor acute lymphoblastic Leukaemia (ETP-ALL).

According to the either side of the application, the transplantable tumor of mouse model can have following cell to lose in the second screening group It is one or more in biography feature or genetics characteristics:A) normal;b)Ph+,t(9;22);c)t(17;19);d)[4]/46, XY[14];e)t(11;19);f)t(4;11);And g) JAK is mutated.

For example, may include in the second screening group it is at least five kinds of (it is at least seven kinds of for example, at least six kinds of, it is at least eight kinds of, at least 9 Kind, at least ten kinds of, at least 11 kinds, at least 12 kinds, at least 13 kinds, at least 14 kinds, at least 15 kinds or more) have represent leukaemia The different mouse models of the transplantable tumor of hypotype BCP-ALL.May include in the second screening group it is at least five kinds of (for example, at least six kinds of, It is at least seven kinds of, at least eight kinds of, at least nine kinds of, at least ten kinds of, at least 11 kinds, at least 12 kinds, at least 13 kinds, at least 14 kinds, at least 15 kinds Or more) the different mouse models with the transplantable tumor for representing leukaemia hypotype T-ALL.May include in the second screening group to Few 5 kinds (for example, at least six kinds of, at least seven kinds of, at least eight kinds of, at least nine kinds of, at least ten kinds of, at least 11 kinds, at least 12 kinds, at least 13 Kind, at least 14 kinds, at least 15 kinds or more) the different mouse models with the transplantable tumor for representing leukaemia hypotype MLL.Described May include in two screening groups it is at least five kinds of (it is at least seven kinds of for example, at least six kinds of, it is at least eight kinds of, it is at least nine kinds of, it is at least ten kinds of, at least 11 Kind, at least 12 kinds, at least 13 kinds, at least 14 kinds, at least 15 kinds or more) there is the transplanting for representing leukaemia hypotype ETP-ALL The different mouse models of tumor.May include in the second screening group it is at least five kinds of (it is at least seven kinds of for example, at least six kinds of, it is at least eight kinds of, At least nine kinds of, at least ten kinds of, at least 11 kinds, at least 12 kinds, at least 13 kinds, at least 14 kinds, at least 15 kinds or more) have comprising The different mouse models of the transplantable tumor of JAK mutation.

For example, in the second screening group, at least one kind of (for example, it is at least two kinds of, it is at least three kinds of, it is at least four kinds of, it is at least five kinds of, It is at least six kinds of, at least seven kinds of, at least eight kinds of, at least nine kinds of, at least ten kinds of, at least 11 kinds, at least 12 kinds, at least 13 kinds, at least 14 kinds, At least 15 kinds or more) transplantable tumor of mouse model may include that JAK is mutated, and the transplantable tumor represents BCP-ALL hypotypes.Described In second screening group, at least one kind of (for example, it is at least two kinds of, it is at least three kinds of, it is at least four kinds of, it is at least five kinds of, it is at least six kinds of, it is at least seven kinds of, until It is 8 kinds few, at least nine kinds of, at least ten kinds of, at least 11 kinds, at least 12 kinds, at least 13 kinds, at least 14 kinds, at least 15 kinds or more) it is small The transplantable tumor of mouse model can have normal Cytogenetic Features, and the transplantable tumor represents BCP-ALL hypotypes or T-ALL is sub- Type.In the second screening group, at least one kind of (for example, it is at least two kinds of, it is at least three kinds of, it is at least four kinds of, it is at least five kinds of, it is at least six kinds of, until Few 7 kinds, at least eight kinds of, at least nine kinds of, at least ten kinds of, at least 11 kinds, at least 12 kinds, at least 13 kinds, at least 14 kinds, at least 15 kinds or More) transplantable tumor of mouse model can have Cytogenetic Features Ph+, t (9;22), and the transplantable tumor represents the Asias BCP-ALL Type.In the second screening group, at least one kind of (for example, it is at least two kinds of, it is at least three kinds of, it is at least four kinds of, it is at least five kinds of, it is at least six kinds of, until Few 7 kinds, at least eight kinds of, at least nine kinds of, at least ten kinds of, at least 11 kinds, at least 12 kinds, at least 13 kinds, at least 14 kinds, at least 15 kinds or More) transplantable tumor of mouse model can have Cytogenetic Features t (17;19), and the transplantable tumor represents BCP-ALL hypotypes. In the second screening group, at least one kind of (for example, it is at least two kinds of, it is at least three kinds of, it is at least four kinds of, it is at least five kinds of, it is at least six kinds of, at least 7 Kind, at least eight kinds of, at least nine kinds of, at least ten kinds of, at least 11 kinds, at least 12 kinds, at least 13 kinds, at least 14 kinds, at least 15 kinds or more It is more) transplantable tumor of mouse model can have Xi Baoyichuanxuetezheng [4]/46,XY[14], and the transplantable tumor represents T-ALL hypotypes. In the second screening group, the transplantable tumor of at least one mouse model can have Cytogenetic Features t (11;It 19), and should Transplantable tumor represents BCP-ALL, T-ALL or MLL hypotype.In the second screening group, at least one kind of (for example, it is at least two kinds of, at least It is 3 kinds, at least four kinds of, at least five kinds of, at least six kinds of, at least seven kinds of, at least eight kinds of, at least nine kinds of, at least ten kinds of, at least 11 kinds, at least 12 Kind, at least 13 kinds, at least 14 kinds, at least 15 kinds or more) transplantable tumor of mouse model can have Cytogenetic Features t (4; Or t (1 11);11), and the transplantable tumor represents BCP-ALL, T-ALL or MLL hypotype.

According to the either side of the application, the transplantable tumor of mouse model may include selected from the group below in the first screening group One or more gene mutations:CREBBP(p.D1481H),EP300(p.Q2268del),FLT3(p.Y572S),MAPK8IP3 (p.D789N),NT5C2(p.R238W),NTRK1(p.G18E),ZNF746(p.R31H),BAI1(p.V536I),BCR (p.E552G),RECQL4(p.A239V),TMPRSS2(p.K353M),ZBTB32(p.P438L),Unknown,ALG8 (p.R41Q),EPHA5(p.S810G),FANCF(p.P117T),MLH1(p.Q460K),MYO3A(p.R1495Q),NRAS (p.G12D),RECQL4(p.R872K),RUNX1(p.Q370R),CSMD3(p.H2714fs),CXCR4(p.F342fs),FAT1 (p.V295M),KRAS(p.L23R),NUP214(p.N1404fs),ALK(p.E1435del),ASXL1(p.D863G),BRCA2 (p.C1290Y),C3orf35(p.A29T),EPHA7(p.K941Q),FBXW7(p.R465C),KDM6A(p.A30T),NT5C2 (p.R367Q),SCN5A(p.R481W),SMARCA4(p.R1189Q),ARID1A(p.P1326_1326P>RT),AURKB (p.V92M),BCL11B(p.R358fs),CSMD3(p.P1581T),EPHA1(p.P460L),MAD1L1(p.E144D), MAP3K2(p.D2_splice),NOTCH1(p.L1600P),PIK3R1(p.202_203insLNQTFP),PML(p.R307C), RPL10(p.R98S),TNK2(p.R751H),FBXW7(p.15_16TR>TLR),HUS1(p.R33H),LIPM(p.T336N), PTEN(p.NSGPTRRED228fs),ALK(p.S15Y),CTCF(p.A648T),EGFR(p.E557Q),EPHB1 (p.T387M),ERBB3(p.Q170fs),ERBB4(p.V949I),SLC44A5(p.M490R),CHEK1(p.I465T), CSF1R (p.S422C), CSMD3 (p.V2959A), FLT3 (p.IM836del), MET (p.L575I), MTO1 (p.R464C) and RET(p.R67H)。

In some embodiments, may include in the first screening group with the shifting for representing leukaemia hypotype BCP-ALL Plant tumor mouse model, and the transplantable tumor for representing leukaemia hypotype BCP-ALL may include it is selected from the group below one or more Gene mutation:CREBBP(p.D1481H),EP300(p.Q2268del),FLT3(p.Y572S),MAPK8IP3(p.D789N), NT5C2(p.R238W),NTRK1(p.G18E),ZNF746(p.R31H),BAI1(p.V536I),BCR(p.E552G),RECQL4 (p.A239V),TMPRSS2(p.K353M),ZBTB32(p.P438L),Unknown,ALG8(p.R41Q),EPHA5 (p.S810G),FANCF(p.P117T),MLH1(p.Q460K),MYO3A(p.R1495Q),NRAS(p.G12D),RECQL4 (p.R872K),RUNX1(p.Q370R),CSMD3(p.H2714fs),CXCR4(p.F342fs),FAT1(p.V295M),KRAS (p.L23R) and NUP214 (p.N1404fs).

For example, the transplantable tumor of the representative leukaemia hypotype BCP-ALL involved in the first screening group may include following base Because of any group in mutation group:

1)CREBBP(p.D1481H),EP300(p.Q2268del),FLT3(p.Y572S),MAPK8IP3(p.D789N), NT5C2 (p.R238W), NTRK1 (p.G18E) and ZNF746 (p.R31H);

2) BAI1 (p.V536I), BCR (p.E552G), RECQL4 (p.A239V), TMPRSS2 (p.K353M) and ZBTB32 (p.P438L);

3)ALG8(p.R41Q),EPHA5(p.S810G),FANCF(p.P117T),MLH1(p.Q460K),MYO3A (p.R1495Q), NRAS (p.G12D), RECQL4 (p.R872K) and RUNX1 (p.Q370R);With

4) CSMD3 (p.H2714fs), CXCR4 (p.F342fs), FAT1 (p.V295M), KRAS (p.L23R) and NUP214 (p.N1404fs)。

In some embodiments, may include in the first screening group with the transplanting for representing leukaemia hypotype T-ALL The mouse model of tumor, and the transplantable tumor for representing leukaemia hypotype T-ALL may include one or more genes selected from the group below Mutation:ALK(p.E1435del),ASXL1(p.D863G),BRCA2(p.C1290Y),C3orf35(p.A29T),EPHA7 (p.K941Q),FBXW7(p.R465C),KDM6A(p.A30T),NT5C2(p.R367Q),SCN5A(p.R481W),SMARCA4 (p.R1189Q),ARID1A(p.P1326_1326P>RT),AURKB(p.V92M),BCL11B(p.R358fs),CSMD3 (p.P1581T),EPHA1(p.P460L),MAD1L1(p.E144D),MAP3K2(p.D2_splice),NOTCH1 (p.L1600P),PIK3R1(p.202_203insLNQTFP),PML(p.R307C),RPL10(p.R98S),TNK2 (p.R751H),FBXW7(p.15_16TR>TLR), HUS1 (p.R33H), LIPM (p.T336N) and PTEN (p.NSGPTRRED228fs)。

For example, the transplantable tumor of the representative leukaemia hypotype T-ALL involved in the first screening group may include following gene Any group in mutation group:

1)ALK(p.E1435del),ASXL1(p.D863G),BRCA2(p.C1290Y),C3orf35(p.A29T), EPHA7 (p.K941Q), FBXW7 (p.R465C), KDM6A (p.A30T), NT5C2 (p.R367Q), SCN5A (p.R481W) and SMARCA4(p.R1189Q);

2)ARID1A(p.P1326_1326P>RT),AURKB(p.V92M),BCL11B(p.R358fs),CSMD3 (p.P1581T),EPHA1(p.P460L),MAD1L1(p.E144D),MAP3K2(p.D2_splice),NOTCH1 (p.L1600P), PIK3R1 (p.202_203insLNQTFP), PML (p.R307C), RPL10 (p.R98S) and TNK2 (p.R751H);With

3)FBXW7(p.15_16TR>TLR), HUS1 (p.R33H), LIPM (p.T336N) and PTEN (p.NSGPTRRED228fs)。

In some embodiments, may include in the first screening group with the transplantable tumor for representing leukaemia hypotype MLL Mouse model, and the transplantable tumor for representing leukaemia hypotype MLL may include one or more gene mutations selected from the group below: ALK(p.S15Y),CTCF(p.A648T),EGFR(p.E557Q),EPHB1(p.T387M),ERBB3(p.Q170fs),ERBB4 (p.V949I),SLC44A5(p.M490R),CHEK1(p.I465T),CSF1R(p.S422C),CSMD3(p.V2959A),FLT3 (p.IM836del), MET (p.L575I), MTO1 (p.R464C) and RET (p.R67H).

For example, the transplantable tumor of the representative leukaemia hypotype MLL involved in the first screening group may include that following gene is prominent Any group in change group:

1)ALK(p.S15Y),CTCF(p.A648T),EGFR(p.E557Q),EPHB1(p.T387M),ERBB3 (p.Q170fs), ERBB4 (p.V949I) and SLC44A5 (p.M490R);With

2)CHEK1(p.I465T),CSF1R(p.S422C),CSMD3(p.V2959A),FLT3(p.IM836del),MET (p.L575I), MTO1 (p.R464C) and RET (p.R67H).

According to the either side of the application, the transplantable tumor of mouse model may include selected from the group below in the second screening group One or more gene mutations:EPHB1(p.E698K),KTN1(p.V1075I),MAPK14(p.T241fs),NOTCH4 (p.L73F),SMARCA4(p.L1531H),TDG(p.T19M),TRIM33(p.V67A),CREBBP(p.1094_1095del) (p.1090_1090del)(p.1087_1089del),CTNNA3(p.R336C),EPHA5(p.M1034L),FAT1 (p.N126fs),JAK1(p.V658L),POLK(p.M364T),STRADB(p.D407G),CREBBP(p.S1934P),FBXW7 (p.R399Q),NOTCH1(p.L1678P),PIK3CD(p.C416R),RBM28(p.Y222F),BAI1/ADGRB1 (p.Q440R),BCL11B(p.E34fs),EPHB3(p.A498T),FAT1(p.G855R),JAK1(p.M206K),NOTCH1 (p.2514_2515del)(p.R1598P),PIK3R5(p.G612S),SMYD1(p.A107E),ABL1(p.623_624del), ATR(p.R2606Q),BRCA2(p.K2729N),FANCA(p.S321T),FZD9(p.I1371S),MLH1(p.V143D), MST4/STK26(p.D19G),SETD2(p.1788_1793del),FBXW7(p.G16delinsPG),HUS1(p.R33H), LIPM(p.T336N),PHOX2B(p.248_254del),PTEN(p.228_236del)*,ABI1(p.239_240del), ABL1(p.E255K),CTCF(c.103-2A>G,splicesite),ITPR3(p.V436M),MLH1(p.K377E),MTOR (p.A461V),NOTCH1(p.L1593P),NOTCH2(p.P2087T),KDM6A(p.V1110fs),NOTCH1(p.N325Y), PIK3CD(p.N334K),CHRND(p.R228C),CREBBP(p.H854P),FANCL(p.T372fs),MAD1L1 (p.R59C),MAPK12(p.G34fs),MARK1(p.P432L),PIK3R3(p.R411L),SGCE(p.P157L),SPEG (p.D1310N),TIE1(p.G850R),HMGA2(p.P92A),MAPK9(p.R59C),SLITRK4(p.V206I),SRF (p.P265S),TYK2(p.A195T),APC(p.R2210G),FAIM2(p.R99H),FAT1(p.L2875V),FLI1 (p.R35L),KCNK17(p.A184T),KRT73(p.T248R),MAP3K1(p.Q237R),RET(p.D567N),AKT1 (p.R465H),HAO2(p.R336W),FAM83A(p.A109T),FAT1(p.I1125L),GMIP(p.A607V),TRIP11 (pG11E),CHEK1(p.I465T),CSF1R(p.S422C),CSMD3(p.V2959A),FLT3(p.837_837del),MET (p.L575I), MTO1 (p.R504C), RET (p.R67H), ATR (p.L2076V), MSH2 (p.E423K) and PRKD1 (p.P33delinsSGP)。

In some embodiments, may include in the second screening group with the shifting for representing leukaemia hypotype BCP-ALL Plant tumor mouse model, and the transplantable tumor for representing leukaemia hypotype BCP-ALL may include it is selected from the group below one or more Gene mutation:EPHB1(p.E698K),KTN1(p.V1075I),MAPK14(p.T241fs),NOTCH4(p.L73F), SMARCA4(p.L1531H),TDG(p.T19M),TRIM33(p.V67A),CREBBP(p.1094_1095del)(p.1090_ 1090del)(p.1087_1089del),CTNNA3(p.R336C),EPHA5(p.M1034L),FAT1(p.N126fs),JAK1 (p.V658L), POLK (p.M364T) and STRADB (p.D407G).

For example, the transplantable tumor of the representative leukaemia hypotype BCP-ALL involved in the second screening group may include following base Because of any group in mutation group:

1)EPHB1(p.E698K),KTN1(p.V1075I),MAPK14(p.T241fs),NOTCH4(p.L73F), SMARCA4 (p.L1531H), TDG (p.T19M) and TRIM33 (p.V67A);With

2)CREBBP(p.1094_1095del)(p.1090_1090del)(p.1087_1089del),CTNNA3 (p.R336C), EPHA5 (p.M1034L), FAT1 (p.N126fs), JAK1 (p.V658L), POLK (p.M364T) and STRADB (p.D407G)。

In some embodiments, may include in the second screening group with the transplanting for representing leukaemia hypotype T-ALL The mouse model of tumor, and the transplantable tumor for representing leukaemia hypotype T-ALL may include one or more genes selected from the group below Mutation:CREBBP(p.S1934P),FBXW7(p.R399Q),NOTCH1(p.L1678P),PIK3CD(p.C416R),RBM28 (p.Y222F),BAI1/ADGRB1(p.Q440R),BCL11B(p.E34fs),EPHB3(p.A498T),FAT1(p.G855R), JAK1(p.M206K),NOTCH1(p.2514_2515del)(p.R1598P),PIK3R5(p.G612S),SMYD1 (p.A107E),ABL1(p.623_624del),ATR(p.R2606Q),BRCA2(p.K2729N),FANCA(p.S321T), FZD9(p.I1371S),MLH1(p.V143D),MST4/STK26(p.D19G),SETD2(p.1788_1793del),FBXW7 (p.G16delinsPG),HUS1(p.R33H),LIPM(p.T336N),PHOX2B(p.248_254del),PTEN(p.228_ 236del)*,ABI1(p.239_240del),ABL1(p.E255K),CTCF(c.103-2A>G,splicesite),ITPR3 (p.V436M),MLH1(p.K377E),MTOR(p.A461V),NOTCH1(p.L1593P),NOTCH2(p.P2087T),KDM6A (p.V1110fs), NOTCH1 (p.N325Y) and PIK3CD (p.N334K).

For example, the transplantable tumor of the representative leukaemia hypotype T-ALL involved in the second screening group may include following gene Any group in mutation group:

1) CREBBP (p.S1934P), FBXW7 (p.R399Q), NOTCH1 (p.L1678P), PIK3CD (p.C416R) and RBM28(p.Y222F);

2)BAI1/ADGRB1(p.Q440R),BCL11B(p.E34fs),EPHB3(p.A498T),FAT1(p.G855R), JAK1 (p.M206K), NOTCH1 (p.2514_2515del) (p.R1598P), PIK3R5 (p.G612S) and SMYD1 (p.A107E);

3)ABL1(p.623_624del),ATR(p.R2606Q),BRCA2(p.K2729N),FANCA(p.S321T), FZD9 (p.I1371S), MLH1 (p.V143D), MST4/STK26 (p.D19G) and SETD2 (p.1788_1793del);

4)FBXW7(p.G16delinsPG),HUS1(p.R33H),LIPM(p.T336N),PHOX2B(p.248_ 254del) and PTEN (p.228_236del) *;

5)ABI1(p.239_240del),ABL1(p.E255K),CTCF(c.103-2A>G),ITPR3(p.V436M), MLH1 (p.K377E), MTOR (p.A461V), NOTCH1 (p.L1593P) and NOTCH2 (p.P2087T);With

6) KDM6A (p.V1110fs), NOTCH1 (p.N325Y8) and PIK3CD (p.N334K).

In some embodiments, may include in the second screening group with the transplantable tumor for representing leukaemia hypotype MLL Mouse model, and the transplantable tumor for representing leukaemia hypotype MLL may include one or more gene mutations selected from the group below: CHRND(p.R228C),CREBBP(p.H854P),FANCL(p.T372fs),MAD1L1(p.R59C),MAPK12 (p.G34fs),MARK1(p.P432L),PIK3R3(p.R411L),SGCE(p.P157L),SPEG(p.D1310N),TIE1 (p.G850R),HMGA2(p.P92A),MAPK9(p.R59C),SLITRK4(p.V206I),SRF(p.P265S),TYK2 (p.A195T),APC(p.R2210G),FAIM2(p.R99H),FAT1(p.L2875V),FLI1(p.R35L),KCNK17 (p.A184T),KRT73(p.T248R),MAP3K1(p.Q237R),RET(p.D567N),AKT1(p.R465H),HAO2 (p.R336W),FAM83A(p.A109T),FAT1(p.I1125L),GMIP(p.A607V),TRIP11(pG11E),CHEK1 (p.I465T),CSF1R(p.S422C),CSMD3(p.V2959A),FLT3(p.837_837del),MET(p.L575I),MTO1 (p.R504C), RET (p.R67H), ATR (p.L2076V), MSH2 (p.E423K) and PRKD1 (p.P33delinsSGP).

For example, the transplantable tumor of the representative leukaemia hypotype MLL involved in the second screening group may include that following gene is prominent Any group in change group:

1) HMGA2 (p.P92A), MAPK9 (p.R59C), SLITRK4 (p.V206I), SRF (p.P265S) and TYK2 (p.A195T);

2)APC(p.R2210G),FAIM2(p.R99H),FAT1(p.L2875V),FLI1(p.R35L),KCNK17 (p.A184T), KRT73 (p.T248R), MAP3K1 (p.Q237R) and RET (p.D567N);

3) AKT1 (p.R465H) and HAO2 (p.R336W);

4) FAM83A (p.A109T), FAT1 (p.I1125L), GMIP (p.A607V) and TRIP11 (pG11E);

5)CHEK1(p.I465T),CSF1R(p.S422C),CSMD3(p.V2959A),FLT3(p.837_837del), MET (p.L575I), MTO1 (p.R504C) and RET (p.R67H);

6)CHRND(p.R228C),CREBBP(p.H854P),FANCL(p.T372fs),MAD1L1(p.R59C), MAPK12 (p.G34fs), MARK1 (p.P432L), PIK3R3 (p.R411L), SGCE (p.P157L), SPEG (p.D1310N) and TIE1(p.G850R);With

7) ATR (p.L2076V), MSH2 (p.E423K) and PRKD1 (p.P33delinsSGP).

System for screening leukemia treating drug candidate provided herein and for being carried out to drug candidate The method of preclinical screening, can accurately and efficiently to leukemia treating drug candidate carry out preclinical screening, so as to so that Those skilled in the art can select suitable drug candidate to carry out clinical test, and improve the efficiency and successfully of clinical test Rate.

Therefore, the application further relates to embodiment in detail below:

1. a kind of method for carrying out Preclinical evaluation to drug candidate, the method includes:

1) in the first screening group the entry evaluation drug candidate validity;And

2) directly the drug candidate is recommended to enter clinical test as a result, determining according to the entry evaluation, or the The validity of the drug candidate is further assessed in all or part of member of two screening groups;

The wherein described first screening group and the second screening group respectively include the transplanting at least one leukaemic source The transplantable tumor of tumor mouse model, each mouse model represents a kind of leukaemia hypotype;

The mouse model is humanized mouse model;And

Leukaemia hypotype in the second screening group representated by the transplantable tumor of mouse model includes all first sieves Select the leukaemia hypotype representated by the transplantable tumor of mouse model in group.

2. according to the method described in embodiment 1, wherein in the first screening group each mouse model transplantable tumor institute source From leukaemic be different from the leukaemic that is originated from of transplantable tumor of each mouse model in the second screening group.

3. according to the method described in any one of embodiment 1-2, wherein the leukaemic is to show drug resistance Leukaemic and/or recurrence leukaemic.

4. according to the method described in any one of embodiment 1-3, wherein the leukaemia includes that acute lymphoblastic is white Blood disease.

5. according to the method described in any one of embodiment 1-4, wherein in the first screening group mouse model shifting The leukaemia hypotype planted representated by tumor includes selected from the group below one or more:The white blood of B cell precursor cell acute lymphocytic Sick (BCP-ALL), T cell acute lymphoblastic leukemia (T-ALL) and mixed lineage leukemia (MLL).

6. according to the method described in any one of embodiment 1-5, wherein in the first screening group mouse model shifting Tumor is planted with one or more in following Cytogenetic Features:

A) normal;

b)Ph+,t(9;22);

c)t(17;19);

d)[4]/46,XY[14];

e)t(11;19);With

f)t(4;11).

7. according to the method described in any one of embodiment 1-6, wherein in the first screening group mouse model shifting Tumor is planted with one or more in following gene mutation:CREBBP(p.D1481H),EP300(p.Q2268del),FLT3 (p.Y572S),MAPK8IP3(p.D789N),NT5C2(p.R238W),NTRK1(p.G18E),ZNF746(p.R31H),BAI1 (p.V536I),BCR(p.E552G),RECQL4(p.A239V),TMPRSS2(p.K353M),ZBTB32(p.P438L), Unknown,ALG8(p.R41Q),EPHA5(p.S810G),FANCF(p.P117T),MLH1(p.Q460K),MYO3A (p.R1495Q),NRAS(p.G12D),RECQL4(p.R872K),RUNX1(p.Q370R),CSMD3(p.H2714fs),CXCR4 (p.F342fs),FAT1(p.V295M),KRAS(p.L23R),NUP214(p.N1404fs),ALK(p.E1435del),ASXL1 (p.D863G),BRCA2(p.C1290Y),C3orf35(p.A29T),EPHA7(p.K941Q),FBXW7(p.R465C),KDM6A (p.A30T),NT5C2(p.R367Q),SCN5A(p.R481W),SMARCA4(p.R1189Q),ARID1A(p.P1326_1326P >RT),AURKB(p.V92M),BCL11B(p.R358fs),CSMD3(p.P1581T),EPHA1(p.P460L),MAD1L1 (p.E144D),MAP3K2(p.D2_splice),NOTCH1(p.L1600P),PIK3R1(p.202_203insLNQTFP),PML (p.R307C),RPL10(p.R98S),TNK2(p.R751H),FBXW7(p.15_16TR>TLR),HUS1(p.R33H),LIPM (p.T336N),PTEN(p.NSGPTRRED228fs),ALK(p.S15Y),CTCF(p.A648T),EGFR(p.E557Q), EPHB1(p.T387M),ERBB3(p.Q170fs),ERBB4(p.V949I),SLC44A5(p.M490R),CHEK1 (p.I465T),CSF1R(p.S422C),CSMD3(p.V2959A),FLT3(p.IM836del),MET(p.L575I),MTO1 (p.R464C) and RET (p.R67H).

8. according to the method described in any one of embodiment 1-7, wherein the first screening group includes at least 50% Different mouse models with the transplantable tumor for representing leukaemia hypotype BCP-ALL.

9. according to the method described in embodiment 8, wherein the transplantable tumor for representing leukaemia hypotype BCP-ALL includes choosing From one or more gene mutations of the following group:CREBBP(p.D1481H),EP300(p.Q2268del),FLT3(p.Y572S), MAPK8IP3(p.D789N),NT5C2(p.R238W),NTRK1(p.G18E),ZNF746(p.R31H),BAI1(p.V536I), BCR(p.E552G),RECQL4(p.A239V),TMPRSS2(p.K353M),ZBTB32(p.P438L),Unknown,ALG8 (p.R41Q),EPHA5(p.S810G),FANCF(p.P117T),MLH1(p.Q460K),MYO3A(p.R1495Q),NRAS (p.G12D),RECQL4(p.R872K),RUNX1(p.Q370R),CSMD3(p.H2714fs),CXCR4(p.F342fs),FAT1 (p.V295M), KRAS (p.L23R) and NUP214 (p.N1404fs).

10. according to the method described in embodiment 9, wherein the transplantable tumor for representing leukaemia hypotype BCP-ALL includes Any group in following gene mutation group:

11. according to the method described in any one of embodiment 8-10, white blood is represented wherein having described at least 50% In the different mouse models of the transplantable tumor of sick hypotype BCP-ALL, at least 30% transplantable tumor has normal cytogenetics special Sign.

12. according to the method described in any one of embodiment 8-11, white blood is represented wherein having described at least 50% In the different mouse models of the transplantable tumor of sick hypotype BCP-ALL, at least 10% transplantable tumor has Cytogenetic Features Ph+, t (9;22).

13. according to the method described in any one of embodiment 8-12, white blood is represented wherein having described at least 50% In the different mouse models of the transplantable tumor of sick hypotype BCP-ALL, at least 10% transplantable tumor has Cytogenetic Features t (17; 19)。

14. according to the method described in any one of embodiment 1-13, wherein the first screening group includes at least 30% has the different mouse models for the transplantable tumor for representing leukaemia hypotype T-ALL.

15. according to the method described in embodiment 14, wherein the transplantable tumor for representing leukaemia hypotype T-ALL includes choosing From one or more gene mutations of the following group:ALK(p.E1435del),ASXL1(p.D863G),BRCA2(p.C1290Y), C3orf35(p.A29T),EPHA7(p.K941Q),FBXW7(p.R465C),KDM6A(p.A30T),NT5C2(p.R367Q), SCN5A(p.R481W),SMARCA4(p.R1189Q),ARID1A(p.P1326_1326P>RT),AURKB(p.V92M), BCL11B(p.R358fs),CSMD3(p.P1581T),EPHA1(p.P460L),MAD1L1(p.E144D),MAP3K2(p.D2_ splice),NOTCH1(p.L1600P),PIK3R1(p.202_203insLNQTFP),PML(p.R307C),RPL10 (p.R98S),TNK2(p.R751H),FBXW7(p.15_16TR>TLR), HUS1 (p.R33H), LIPM (p.T336N) and PTEN (p.NSGPTRRED228fs)。

16. according to the method described in embodiment 15, wherein the transplantable tumor for representing leukaemia hypotype T-ALL includes such as Any group in lower gene mutation group:

17. according to the method described in any one of embodiment 14-16, white blood is represented wherein having described at least 30% In the different mouse models of the transplantable tumor of sick hypotype T-ALL, at least 10% transplantable tumor has normal Cytogenetic Features.

18. according to the method described in any one of embodiment 14-17, white blood is represented wherein having described at least 30% In the different mouse models of the transplantable tumor of sick hypotype T-ALL, at least 10% transplantable tumor has Xi Baoyichuanxuetezheng [4]/46, XY[14]。

19. according to the method described in any one of embodiment 1-18, wherein the first screening group includes at least 20% has the different mouse models for the transplantable tumor for representing leukaemia hypotype MLL.

20. according to the method described in embodiment 19, wherein the transplantable tumor for representing leukaemia hypotype MLL includes being selected from One or more gene mutations of the following group:ALK(p.S15Y),CTCF(p.A648T),EGFR(p.E557Q),EPHB1 (p.T387M),ERBB3(p.Q170fs),ERBB4(p.V949I),SLC44A5(p.M490R),CHEK1(p.I465T), CSF1R (p.S422C), CSMD3 (p.V2959A), FLT3 (p.IM836del), MET (p.L575I), MTO1 (p.R464C) and RET(p.R67H)。

21. according to the method described in embodiment 20, wherein the transplantable tumor for representing leukaemia hypotype MLL includes as follows Any group in gene mutation group:

22. according to the method described in any one of embodiment 19-21, white blood is represented wherein having described at least 20% In the different mouse models of the transplantable tumor of sick hypotype MLL, at least 10% transplantable tumor has Cytogenetic Features t (11;19).

23. according to the method described in any one of embodiment 19-22, white blood is represented wherein having described at least 20% In the different mouse models of the transplantable tumor of sick hypotype MLL, at least 10% transplantable tumor has Cytogenetic Features t (4;11).

24. according to the method described in any one of embodiment 1-23, wherein for mouse mould in the first screening group Each leukaemia hypotype representated by the transplantable tumor of type includes with the transplanting for representing the hypotype in the second screening group Two or more mouse models of tumor.

25. according to the method described in any one of embodiment 1-24, wherein mouse model in the second screening group Leukaemia hypotype representated by transplantable tumor includes selected from the group below one or more:BCP-ALL, T-ALL, MLL and Pre-Tcell Precursor acute lymphoblastic leukemia (ETP-ALL).

26. according to the method described in any one of embodiment 1-25, wherein mouse model in the second screening group Transplantable tumor is with one or more in following Cytogenetic Features or genetics characteristics:

A) normal;

b)Ph+,t(9;22);

c)t(17;19);

d)[4]/46,XY[14];

e)t(11;19);

f)t(1;11);

g)t(4;11);With

H) JAK is mutated.

27. according to the method described in any one of embodiment 1-26, wherein mouse model in the second screening group Transplantable tumor has one or more in following gene mutation:EPHB1(p.E698K),KTN1(p.V1075I),MAPK14 (p.T241fs),NOTCH4(p.L73F),SMARCA4(p.L1531H),TDG(p.T19M),TRIM33(p.V67A),CREBBP (p.1094_1095del)(p.1090_1090del)(p.1087_1089del),CTNNA3(p.R336C),EPHA5 (p.M1034L),FAT1(p.N126fs),JAK1(p.V658L),POLK(p.M364T),STRADB(p.D407G),CREBBP (p.S1934P),FBXW7(p.R399Q),NOTCH1(p.L1678P),PIK3CD(p.C416R),RBM28(p.Y222F), BAI1/ADGRB1(p.Q440R),BCL11B(p.E34fs),EPHB3(p.A498T),FAT1(p.G855R),JAK1 (p.M206K),NOTCH1(p.2514_2515del)(p.R1598P),PIK3R5(p.G612S),SMYD1(p.A107E), ABL1(p.623_624del),ATR(p.R2606Q),BRCA2(p.K2729N),FANCA(p.S321T),FZD9 (p.I1371S),MLH1(p.V143D),MST4/STK26(p.D19G),SETD2(p.1788_1793del),FBXW7 (p.G16delinsPG),HUS1(p.R33H),LIPM(p.T336N),PHOX2B(p.248_254del),PTEN(p.228_ 236del)*,ABI1(p.239_240del),ABL1(p.E255K),CTCF(c.103-2A>G,splicesite),ITPR3 (p.V436M),MLH1(p.K377E),MTOR(p.A461V),NOTCH1(p.L1593P),NOTCH2(p.P2087T),KDM6A (p.V1110fs),NOTCH1(p.N325Y),PIK3CD(p.N334K),CHRND(p.R228C),CREBBP(p.H854P), FANCL(p.T372fs),MAD1L1(p.R59C),MAPK12(p.G34fs),MARK1(p.P432L),PIK3R3 (p.R411L),SGCE(p.P157L),SPEG(p.D1310N),TIE1(p.G850R),HMGA2(p.P92A),MAPK9 (p.R59C),SLITRK4(p.V206I),SRF(p.P265S),TYK2(p.A195T),APC(p.R2210G),FAIM2 (p.R99H),FAT1(p.L2875V),FLI1(p.R35L),KCNK17(p.A184T),KRT73(p.T248R),MAP3K1 (p.Q237R),RET(p.D567N),AKT1(p.R465H),HAO2(p.R336W),FAM83A(p.A109T),FAT1 (p.I1125L),GMIP(p.A607V),TRIP11(pG11E),CHEK1(p.I465T),CSF1R(p.S422C),CSMD3 (p.V2959A),FLT3(p.837_837del),MET(p.L575I),MTO1(p.R504C),RET(p.R67H),ATR (p.L2076V), MSH2 (p.E423K) and PRKD1 (p.P33delinsSGP).

28. according to the method described in any one of embodiment 1-27, wherein the second screening group includes at least 10 Kind has the different mouse models for the transplantable tumor for representing leukaemia hypotype BCP-ALL.

29. according to the method described in embodiment 28, wherein the transplantable tumor for representing leukaemia hypotype BCP-ALL includes One or more gene mutations selected from the group below:EPHB1(p.E698K),KTN1(p.V1075I),MAPK14(p.T241fs), NOTCH4(p.L73F),SMARCA4(p.L1531H),TDG(p.T19M),TRIM33(p.V67A),CREBBP(p.1094_ 1095del)(p.1090_1090del)(p.1087_1089del),CTNNA3(p.R336C),EPHA5(p.M1034L),FAT1 (p.N126fs), JAK1 (p.V658L), POLK (p.M364T) and STRADB (p.D407G).

30. according to the method described in embodiment 29, wherein the transplantable tumor for representing leukaemia hypotype BCP-ALL includes Any group in following gene mutation group:

31. according to the method described in any one of embodiment 1-30, wherein the second screening group includes at least 10 Kind has the different mouse models for the transplantable tumor for representing leukaemia hypotype T-ALL.

32. according to the method described in embodiment 31, wherein the transplantable tumor for representing leukaemia hypotype T-ALL includes choosing From one or more gene mutations of the following group:CREBBP(p.S1934P),FBXW7(p.R399Q),NOTCH1(p.L1678P), PIK3CD(p.C416R),RBM28(p.Y222F),BAI1/ADGRB1(p.Q440R),BCL11B(p.E34fs),EPHB3 (p.A498T),FAT1(p.G855R),JAK1(p.M206K),NOTCH1(p.2514_2515del)(p.R1598P),PIK3R5 (p.G612S),SMYD1(p.A107E),ABL1(p.623_624del),ATR(p.R2606Q),BRCA2(p.K2729N), FANCA(p.S321T),FZD9(p.I1371S),MLH1(p.V143D),MST4/STK26(p.D19G),SETD2(p.1788_ 1793del),FBXW7(p.G16delinsPG),HUS1(p.R33H),LIPM(p.T336N),PHOX2B(p.248_ 254del),PTEN(p.228_236del)*,ABI1(p.239_240del),ABL1(p.E255K),CTCF(c.103-2A>G, splicesite),ITPR3(p.V436M),MLH1(p.K377E),MTOR(p.A461V),NOTCH1(p.L1593P), NOTCH2 (p.P2087T), KDM6A (p.V1110fs), NOTCH1 (p.N325Y) and PIK3CD (p.N334K).

33. according to the method described in embodiment 32, wherein the transplantable tumor for representing leukaemia hypotype T-ALL includes such as Any group in lower gene mutation group:

6) KDM6A (p.V1110fs), NOTCH1 (p.N325Y8) and PIK3CD (p.N334K).

34. according to the method described in any one of embodiment 1-33, wherein the second screening group includes at least seven kinds of Different mouse models with the transplantable tumor for representing leukaemia hypotype MLL.

35. according to the method described in embodiment 34, wherein the transplantable tumor for representing leukaemia hypotype MLL includes being selected from One or more gene mutations of the following group:CHRND(p.R228C),CREBBP(p.H854P),FANCL(p.T372fs), MAD1L1(p.R59C),MAPK12(p.G34fs),MARK1(p.P432L),PIK3R3(p.R411L),SGCE(p.P157L), SPEG(p.D1310N),TIE1(p.G850R),HMGA2(p.P92A),MAPK9(p.R59C),SLITRK4(p.V206I),SRF (p.P265S),TYK2(p.A195T),APC(p.R2210G),FAIM2(p.R99H),FAT1(p.L2875V),FLI1 (p.R35L),KCNK17(p.A184T),KRT73(p.T248R),MAP3K1(p.Q237R),RET(p.D567N),AKT1 (p.R465H),HAO2(p.R336W),FAM83A(p.A109T),FAT1(p.I1125L),GMIP(p.A607V),TRIP11 (pG11E),CHEK1(p.I465T),CSF1R(p.S422C),CSMD3(p.V2959A),FLT3(p.837_837del),MET (p.L575I), MTO1 (p.R504C), RET (p.R67H), ATR (p.L2076V), MSH2 (p.E423K) and PRKD1 (p.P33delinsSGP)。

36. according to the method described in embodiment 35, wherein the transplantable tumor for representing leukaemia hypotype MLL includes as follows Any group in gene mutation group:

3) AKT1 (p.R465H) and HAO2 (p.R336W);

4) FAM83A (p.A109T), FAT1 (p.I1125L), GMIP (p.A607V) and TRIP11 (pG11E);

7) ATR (p.L2076V), MSH2 (p.E423K) and PRKD1 (p.P33delinsSGP).

37. according to the method described in any one of embodiment 1-36, wherein the second screening group includes at least six kinds of Different mouse models with the transplantable tumor for representing leukaemia hypotype ETP-ALL.

38. according to the method described in any one of embodiment 1-37, wherein the second screening group includes at least 10 Kind has the different mouse models for including the JAK transplantable tumors being mutated.

39. according to the method described in any one of embodiment 26-38, wherein in the second screening group, at least one The transplantable tumor of kind mouse model includes that JAK is mutated, and the transplantable tumor represents BCP-ALL hypotypes.

40. according to the method described in any one of embodiment 26-39, wherein in the second screening group, at least one The transplantable tumor of kind mouse model has normal Cytogenetic Features, and the transplantable tumor represents BCP-ALL hypotypes or T-ALL is sub- Type.

41. according to the method described in any one of embodiment 26-40, wherein in the second screening group, at least one The transplantable tumor of kind mouse model has Cytogenetic Features Ph+, t (9;22), and the transplantable tumor represents BCP-ALL hypotypes.

42. according to the method described in any one of embodiment 26-41, wherein in the second screening group, at least one The transplantable tumor of kind mouse model has Cytogenetic Features t (17;19), and the transplantable tumor represents BCP-ALL hypotypes.

43. according to the method described in any one of embodiment 26-42, wherein in the second screening group, at least one The transplantable tumor of kind mouse model has Xi Baoyichuanxuetezheng [4]/46,XY[14], and the transplantable tumor represents T-ALL hypotypes.

44. according to the method described in any one of embodiment 26-43, wherein in the second screening group, at least one The transplantable tumor of kind mouse model has Cytogenetic Features t (11;19), and the transplantable tumor represents BCP-ALL, T-ALL or MLL Hypotype.

45. according to the method described in any one of embodiment 26-44, wherein in the second screening group, at least one The transplantable tumor of kind mouse model has Cytogenetic Features t (4;Or t (1 11);11), and the transplantable tumor represents BCP-ALL, T- ALL or MLL hypotypes.

46. according to the method described in any one of embodiment 1-45, wherein the entry evaluation drug candidate is effective Property includes:All transplantable tumor mouse models into the first screening group apply suitable drug candidate respectively, and supervise Survey ratio of the leukaemia cell in each transplantable tumor mouse model peripheral blood cells, when the ratio maintain below about 1% to When about 2 weeks few, judge that the drug candidate is effective.

47. according to the method described in any one of embodiment 1-46, wherein be directed in the entry evaluation to described At least 80% transplantable tumor mouse model shows effective drug candidate in first screening group, be determined as 1) directly recommending into Enter clinical test;Or 2) in all or part of member of the second screening group further assess the effective of the drug candidate Property.

48. according to the method described in any one of embodiment 1-47, wherein be directed in the entry evaluation to described 80% transplantable tumor mouse model below shows effective drug candidate in first screening group, in the whole of the second screening group Or the validity of the drug candidate is further assessed in few members.

49. according to the method described in embodiment 48, wherein in the first screening group in the entry evaluation 80% transplantable tumor mouse model below shows that the effective drug candidate is the targeted drug for specific target spot, and described Method includes:It selects to be positive transplantable tumor mouse model to the specific target spot from the second screening group, and selected The validity of the drug candidate is further assessed in the transplantable tumor mouse model selected.

50. according to the method described in embodiment 49, wherein the drug candidate in the entry evaluation to described 50% or more and 80% transplantable tumor mouse model below is shown effectively in one screening group, and the drug candidate is described first Be more than in screening group the 80% specific leukaemia hypotype of representative transplantable tumor mouse model in effectively, and the method includes: It is represented in second screening group in the transplantable tumor mouse model of the specific leukaemia hypotype and further assesses the effective of the drug candidate Property.

51. according to the method described in any one of embodiment 1-50, wherein the drug candidate presses down selected from protein kinase Preparation, apoptosis regulators promote gene splitting drug, cell division inhibitor, MDM2 class oncogene inhibitor, antibody class Drug and/or other chemotherapeutics additives.

52. according to the method described in embodiment 51, wherein the kinases inhibitor includes AZD8055, MLN0128, GSK690693, MK-2206, SAR245408, rapamycin, MLN0128, selumetinib, AZD6244, PCI-32765, ibrutinib, SGI-1776, dinaciclib, VS-4718, temsirolimus, sorafenib, Sunitinib, ruxolitinib, AZD1480 and/or dasatinib.

53. according to the method described in any one of embodiment 51-52, wherein the apoptosis regulators include ABT- 263 (navitoclax), ABT-199 (venetoclax), LCL161 and/or birinapant.

54. according to the method described in any one of embodiment 51-53, wherein the MDM2 classes oncogene inhibitor packet Include MK-8242 (SCH 900242) and/or RG7112.

55. according to the method described in any one of embodiment 51-54, wherein the rush gene splitting drug includes PR- 104, cytarabine (CPX-351), daunorubicin (Vyxeos), topotecan, clofarabine and/or temozolomide。

56. according to the method described in any one of embodiment 51-55, wherein the cell division inhibitor includes Eribulin, ispinesib, bortezomib, carfilzomib and/or alisertib.

57. according to the method described in any one of embodiment 51-56, wherein the antibody class drug includes SAR3419, Blinatumomab and/or inotuzumab.

58. according to the method described in any one of embodiment 51-57, wherein other described chemotherapeutics additives include Alvespimycin, AT13387, PF-03084014, RO-4929097, MLN4924, PG11047, CX-5461, BMN-673, Selinexor, curaxin and/or CBL0137.

59. according to the method described in any one of embodiment 51-58, wherein the drug candidate may also include in the following group It is one or more:Vincristine, dexamethasone, cyclophosphamide, vincristine, dexamethasone and leunase group It closes, NSC750854, topotecan, Volasertib, Serdemetan, JNJ-26481585 and KTP-330.

60. a kind of system for assessing leukemia treating drug candidate, the system comprises the first screening group and second Screening group, wherein:

The first screening group and the second screening group include respectively that the transplantable tumor at least one leukaemic source is small The transplantable tumor of mouse model, each mouse model represents a kind of leukaemia hypotype;

The mouse model is humanized mouse model;And

61. according to the system described in embodiment 60, wherein in the first screening group each mouse model transplantable tumor institute The leukaemic being originated from is different from the leukaemic that the transplantable tumor of each mouse model in the second screening group is originated from.

62. according to the system described in any one of embodiment 60-61, wherein the leukaemic is to show anti-medicine The leukaemic of property and/or the leukaemic of recurrence.

63. according to the system described in any one of embodiment 60-62, wherein the leukaemia includes acute lymphoblastic Leukaemia.

64. according to the system described in any one of embodiment 60-63, wherein mouse model in the first screening group Leukaemia hypotype representated by transplantable tumor includes selected from the group below one or more:B cell precursor cell acute lymphocytic is white Blood disease (BCP-ALL), T cell acute lymphoblastic leukemia (T-ALL) and mixed lineage leukemia (MLL).

65. according to the system described in any one of embodiment 60-64, wherein mouse model in the first screening group Transplantable tumor has one or more in following Cytogenetic Features:

A) normal;

b)Ph+,t(9;22);

c)t(17;19);

d)[4]/46,XY[14];

e)t(11;19);With

f)t(4;11).

66. according to the system described in any one of embodiment 60-65, wherein mouse model in the first screening group Transplantable tumor has one or more in following gene mutation:CREBBP(p.D1481H),EP300(p.Q2268del),FLT3 (p.Y572S),MAPK8IP3(p.D789N),NT5C2(p.R238W),NTRK1(p.G18E),ZNF746(p.R31H),BAI1 (p.V536I),BCR(p.E552G),RECQL4(p.A239V),TMPRSS2(p.K353M),ZBTB32(p.P438L), Unknown,ALG8(p.R41Q),EPHA5(p.S810G),FANCF(p.P117T),MLH1(p.Q460K),MYO3A (p.R1495Q),NRAS(p.G12D),RECQL4(p.R872K),RUNX1(p.Q370R),CSMD3(p.H2714fs),CXCR4 (p.F342fs),FAT1(p.V295M),KRAS(p.L23R),NUP214(p.N1404fs),ALK(p.E1435del),ASXL1 (p.D863G),BRCA2(p.C1290Y),C3orf35(p.A29T),EPHA7(p.K941Q),FBXW7(p.R465C),KDM6A (p.A30T),NT5C2(p.R367Q),SCN5A(p.R481W),SMARCA4(p.R1189Q),ARID1A(p.P1326_1326P >RT),AURKB(p.V92M),BCL11B(p.R358fs),CSMD3(p.P1581T),EPHA1(p.P460L),MAD1L1 (p.E144D),MAP3K2(p.D2_splice),NOTCH1(p.L1600P),PIK3R1(p.202_203insLNQTFP),PML (p.R307C),RPL10(p.R98S),TNK2(p.R751H),FBXW7(p.15_16TR>TLR),HUS1(p.R33H),LIPM (p.T336N),PTEN(p.NSGPTRRED228fs),ALK(p.S15Y),CTCF(p.A648T),EGFR(p.E557Q), EPHB1(p.T387M),ERBB3(p.Q170fs),ERBB4(p.V949I),SLC44A5(p.M490R),CHEK1 (p.I465T),CSF1R(p.S422C),CSMD3(p.V2959A),FLT3(p.IM836del),MET(p.L575I),MTO1 (p.R464C) and RET (p.R67H).

67. according to the system described in any one of embodiment 60-66, wherein the first screening group includes at least 50% has the different mouse models for the transplantable tumor for representing leukaemia hypotype BCP-ALL.

68. according to the system described in embodiment 67, wherein the transplantable tumor for representing leukaemia hypotype BCP-ALL includes One or more gene mutations selected from the group below:CREBBP(p.D1481H),EP300(p.Q2268del),FLT3 (p.Y572S),MAPK8IP3(p.D789N),NT5C2(p.R238W),NTRK1(p.G18E),ZNF746(p.R31H),BAI1 (p.V536I),BCR(p.E552G),RECQL4(p.A239V),TMPRSS2(p.K353M),ZBTB32(p.P438L), Unknown,ALG8(p.R41Q),EPHA5(p.S810G),FANCF(p.P117T),MLH1(p.Q460K),MYO3A (p.R1495Q),NRAS(p.G12D),RECQL4(p.R872K),RUNX1(p.Q370R),CSMD3(p.H2714fs),CXCR4 (p.F342fs), FAT1 (p.V295M), KRAS (p.L23R) and NUP214 (p.N1404fs).

69. according to the system described in embodiment 68, wherein the transplantable tumor for representing leukaemia hypotype BCP-ALL includes Any group in following gene mutation group:

70. according to the system described in any one of embodiment 67-69, white blood is represented wherein having described at least 50% In the different mouse models of the transplantable tumor of sick hypotype BCP-ALL, at least 30% transplantable tumor has normal cytogenetics special Sign.

71. according to the system described in any one of embodiment 67-70, white blood is represented wherein having described at least 50% In the different mouse models of the transplantable tumor of sick hypotype BCP-ALL, at least 10% transplantable tumor has Cytogenetic Features Ph+, t (9;22).

72. according to the system described in any one of embodiment 67-71, white blood is represented wherein having described at least 50% In the different mouse models of the transplantable tumor of sick hypotype BCP-ALL, at least 10% transplantable tumor has Cytogenetic Features t (17; 19)。

73. according to the system described in any one of embodiment 60-72, wherein the first screening group includes at least 30% has the different mouse models for the transplantable tumor for representing leukaemia hypotype T-ALL.

74. according to the system described in embodiment 73, wherein the transplantable tumor for representing leukaemia hypotype T-ALL includes choosing From one or more gene mutations of the following group:ALK(p.E1435del),ASXL1(p.D863G),BRCA2(p.C1290Y), C3orf35(p.A29T),EPHA7(p.K941Q),FBXW7(p.R465C),KDM6A(p.A30T),NT5C2(p.R367Q), SCN5A(p.R481W),SMARCA4(p.R1189Q),ARID1A(p.P1326_1326P>RT),AURKB(p.V92M), BCL11B(p.R358fs),CSMD3(p.P1581T),EPHA1(p.P460L),MAD1L1(p.E144D),MAP3K2(p.D2_ splice),NOTCH1(p.L1600P),PIK3R1(p.202_203insLNQTFP),PML(p.R307C),RPL10 (p.R98S),TNK2(p.R751H),FBXW7(p.15_16TR>TLR), HUS1 (p.R33H), LIPM (p.T336N) and PTEN (p.NSGPTRRED228fs)。

75. according to the system described in embodiment 74, wherein the transplantable tumor for representing leukaemia hypotype T-ALL includes such as Any group in lower gene mutation group:

76. according to the system described in any one of embodiment 73-75, white blood is represented wherein having described at least 30% In the different mouse models of the transplantable tumor of sick hypotype T-ALL, at least 10% transplantable tumor has normal Cytogenetic Features.

77. according to the system described in any one of embodiment 73-76, white blood is represented wherein having described at least 30% In the different mouse models of the transplantable tumor of sick hypotype T-ALL, at least 10% transplantable tumor has Xi Baoyichuanxuetezheng [4]/46, XY[14]。

78. according to the system described in any one of embodiment 60-77, wherein the first screening group includes at least 20% has the different mouse models for the transplantable tumor for representing leukaemia hypotype MLL.

79. according to the system described in embodiment 78, wherein the transplantable tumor for representing leukaemia hypotype MLL includes being selected from One or more gene mutations of the following group:ALK(p.S15Y),CTCF(p.A648T),EGFR(p.E557Q),EPHB1 (p.T387M),ERBB3(p.Q170fs),ERBB4(p.V949I),SLC44A5(p.M490R),CHEK1(p.I465T), CSF1R (p.S422C), CSMD3 (p.V2959A), FLT3 (p.IM836del), MET (p.L575I), MTO1 (p.R464C) and RET(p.R67H)。

80. according to the system described in embodiment 79, wherein the transplantable tumor for representing leukaemia hypotype MLL includes as follows Any group in gene mutation group:

81. according to the system described in any one of embodiment 78-80, white blood is represented wherein having described at least 20% In the different mouse models of the transplantable tumor of sick hypotype MLL, at least 10% transplantable tumor has Cytogenetic Features t (11;19).

82. according to the system described in any one of embodiment 78-81, white blood is represented wherein having described at least 20% In the different mouse models of the transplantable tumor of sick hypotype MLL, at least 10% transplantable tumor has Cytogenetic Features t (4;11).

83. according to the system described in any one of embodiment 60-82, wherein for mouse mould in the first screening group Each leukaemia hypotype representated by the transplantable tumor of type includes with the transplanting for representing the hypotype in the second screening group Two or more mouse models of tumor.

84. according to the system described in any one of embodiment 60-83, wherein mouse model in the second screening group Leukaemia hypotype representated by transplantable tumor includes selected from the group below one or more:BCP-ALL, T-ALL, MLL and Pre-Tcell Precursor acute lymphoblastic leukemia (ETP-ALL).

85. according to the system described in any one of embodiment 60-84, wherein mouse model in the second screening group Transplantable tumor is with one or more in following Cytogenetic Features or genetics characteristics:

A) normal;

b)Ph+,t(9;22);

c)t(17;19);

d)[4]/46,XY[14];

e)t(11;19);

f)t(1;11);

g)t(4;11);With

H) JAK is mutated.

86. according to the system described in any one of embodiment 60-85, wherein mouse model in the second screening group Transplantable tumor has one or more in following gene mutation:EPHB1(p.E698K),KTN1(p.V1075I),MAPK14 (p.T241fs),NOTCH4(p.L73F),SMARCA4(p.L1531H),TDG(p.T19M),TRIM33(p.V67A),CREBBP (p.1094_1095del)(p.1090_1090del)(p.1087_1089del),CTNNA3(p.R336C),EPHA5 (p.M1034L),FAT1(p.N126fs),JAK1(p.V658L),POLK(p.M364T),STRADB(p.D407G),CREBBP (p.S1934P),FBXW7(p.R399Q),NOTCH1(p.L1678P),PIK3CD(p.C416R),RBM28(p.Y222F), BAI1/ADGRB1(p.Q440R),BCL11B(p.E34fs),EPHB3(p.A498T),FAT1(p.G855R),JAK1 (p.M206K),NOTCH1(p.2514_2515del)(p.R1598P),PIK3R5(p.G612S),SMYD1(p.A107E), ABL1(p.623_624del),ATR(p.R2606Q),BRCA2(p.K2729N),FANCA(p.S321T),FZD9 (p.I1371S),MLH1(p.V143D),MST4/STK26(p.D19G),SETD2(p.1788_1793del),FBXW7 (p.G16delinsPG),HUS1(p.R33H),LIPM(p.T336N),PHOX2B(p.248_254del),PTEN(p.228_ 236del)*,ABI1(p.239_240del),ABL1(p.E255K),CTCF(c.103-2A>G,splicesite),ITPR3 (p.V436M),MLH1(p.K377E),MTOR(p.A461V),NOTCH1(p.L1593P),NOTCH2(p.P2087T),KDM6A (p.V1110fs),NOTCH1(p.N325Y),PIK3CD(p.N334K),CHRND(p.R228C),CREBBP(p.H854P), FANCL(p.T372fs),MAD1L1(p.R59C),MAPK12(p.G34fs),MARK1(p.P432L),PIK3R3 (p.R411L),SGCE(p.P157L),SPEG(p.D1310N),TIE1(p.G850R),HMGA2(p.P92A),MAPK9 (p.R59C),SLITRK4(p.V206I),SRF(p.P265S),TYK2(p.A195T),APC(p.R2210G),FAIM2 (p.R99H),FAT1(p.L2875V),FLI1(p.R35L),KCNK17(p.A184T),KRT73(p.T248R),MAP3K1 (p.Q237R),RET(p.D567N),AKT1(p.R465H),HAO2(p.R336W),FAM83A(p.A109T),FAT1 (p.I1125L),GMIP(p.A607V),TRIP11(pG11E),CHEK1(p.I465T),CSF1R(p.S422C),CSMD3 (p.V2959A),FLT3(p.837_837del),MET(p.L575I),MTO1(p.R504C),RET(p.R67H),ATR (p.L2076V), MSH2 (p.E423K) and PRKD1 (p.P33delinsSGP).

87. according to the system described in any one of embodiment 60-86, wherein the second screening group includes at least 10 Kind has the different mouse models for the transplantable tumor for representing leukaemia hypotype BCP-ALL.

88. according to the system described in embodiment 87, wherein the transplantable tumor for representing leukaemia hypotype BCP-ALL includes One or more gene mutations selected from the group below:EPHB1(p.E698K),KTN1(p.V1075I),MAPK14(p.T241fs), NOTCH4(p.L73F),SMARCA4(p.L1531H),TDG(p.T19M),TRIM33(p.V67A),CREBBP(p.1094_ 1095del)(p.1090_1090del)(p.1087_1089del),CTNNA3(p.R336C),EPHA5(p.M1034L),FAT1 (p.N126fs), JAK1 (p.V658L), POLK (p.M364T) and STRADB (p.D407G).

89. according to the system described in embodiment 88, wherein the transplantable tumor for representing leukaemia hypotype BCP-ALL includes Any group in following gene mutation group:

90. according to the system described in any one of embodiment 60-89, wherein the second screening group includes at least 10 Kind has the different mouse models for the transplantable tumor for representing leukaemia hypotype T-ALL.

91. according to the system described in embodiment 90, wherein the transplantable tumor for representing leukaemia hypotype T-ALL includes choosing From one or more gene mutations of the following group:CREBBP(p.S1934P),FBXW7(p.R399Q),NOTCH1(p.L1678P), PIK3CD(p.C416R),RBM28(p.Y222F),BAI1/ADGRB1(p.Q440R),BCL11B(p.E34fs),EPHB3 (p.A498T),FAT1(p.G855R),JAK1(p.M206K),NOTCH1(p.2514_2515del)(p.R1598P),PIK3R5 (p.G612S),SMYD1(p.A107E),ABL1(p.623_624del),ATR(p.R2606Q),BRCA2(p.K2729N), FANCA(p.S321T),FZD9(p.I1371S),MLH1(p.V143D),MST4/STK26(p.D19G),SETD2(p.1788_ 1793del),FBXW7(p.G16delinsPG),HUS1(p.R33H),LIPM(p.T336N),PHOX2B(p.248_ 254del),PTEN(p.228_236del)*,ABI1(p.239_240del),ABL1(p.E255K),CTCF(c.103-2A>G, splicesite),ITPR3(p.V436M),MLH1(p.K377E),MTOR(p.A461V),NOTCH1(p.L1593P), NOTCH2 (p.P2087T), KDM6A (p.V1110fs), NOTCH1 (p.N325Y) and PIK3CD (p.N334K).

92. according to the system described in embodiment 91, wherein the transplantable tumor for representing leukaemia hypotype T-ALL includes such as Any group in lower gene mutation group:

6) KDM6A (p.V1110fs), NOTCH1 (p.N325Y8) and PIK3CD (p.N334K).

93. according to the system described in any one of embodiment 60-92, wherein the second screening group includes at least 7 Kind has the different mouse models for the transplantable tumor for representing leukaemia hypotype MLL.

94. according to the system described in embodiment 93, wherein the transplantable tumor for representing leukaemia hypotype MLL includes being selected from One or more gene mutations of the following group:CHRND(p.R228C),CREBBP(p.H854P),FANCL(p.T372fs), MAD1L1(p.R59C),MAPK12(p.G34fs),MARK1(p.P432L),PIK3R3(p.R411L),SGCE(p.P157L), SPEG(p.D1310N),TIE1(p.G850R),HMGA2(p.P92A),MAPK9(p.R59C),SLITRK4(p.V206I),SRF (p.P265S),TYK2(p.A195T),APC(p.R2210G),FAIM2(p.R99H),FAT1(p.L2875V),FLI1 (p.R35L),KCNK17(p.A184T),KRT73(p.T248R),MAP3K1(p.Q237R),RET(p.D567N),AKT1 (p.R465H),HAO2(p.R336W),FAM83A(p.A109T),FAT1(p.I1125L),GMIP(p.A607V),TRIP11 (pG11E),CHEK1(p.I465T),CSF1R(p.S422C),CSMD3(p.V2959A),FLT3(p.837_837del),MET (p.L575I), MTO1 (p.R504C), RET (p.R67H), ATR (p.L2076V), MSH2 (p.E423K) and PRKD1 (p.P33delinsSGP)。

95. according to the system described in embodiment 94, wherein the transplantable tumor for representing leukaemia hypotype MLL includes as follows Any group in gene mutation group:

3) AKT1 (p.R465H) and HAO2 (p.R336W);

4) FAM83A (p.A109T), FAT1 (p.I1125L), GMIP (p.A607V) and TRIP11 (pG11E);

7) ATR (p.L2076V), MSH2 (p.E423K) and PRKD1 (p.P33delinsSGP).

96. according to the system described in any one of embodiment 60-95, wherein the second screening group includes at least 6 Kind has the different mouse models for the transplantable tumor for representing leukaemia hypotype ETP-ALL.

97. according to the system described in any one of embodiment 60-96, wherein the second screening group includes at least 10 Kind has the different mouse models for including the JAK transplantable tumors being mutated.

98. according to the system described in any one of embodiment 85-97, wherein in the second screening group, at least one The transplantable tumor of kind mouse model includes that JAK is mutated, and the transplantable tumor represents BCP-ALL hypotypes.

99. according to the system described in any one of embodiment 85-98, wherein in the second screening group, at least one The transplantable tumor of kind mouse model has normal Cytogenetic Features, and the transplantable tumor represents BCP-ALL hypotypes or T-ALL is sub- Type.

100. according to the system described in any one of embodiment 85-99, wherein in the second screening group, at least one The transplantable tumor of kind mouse model has Cytogenetic Features Ph+, t (9;22), and the transplantable tumor represents BCP-ALL hypotypes.

101. according to the system described in any one of embodiment 85-100, wherein in the second screening group, at least A kind of transplantable tumor of mouse model has Cytogenetic Features t (17;19), and the transplantable tumor represents BCP-ALL hypotypes.

102. according to the system described in any one of embodiment 85-101, wherein in the second screening group, at least A kind of transplantable tumor of mouse model has Xi Baoyichuanxuetezheng [4]/46,XY[14], and the transplantable tumor represents T-ALL hypotypes.

103. according to the system described in any one of embodiment 85-102, wherein in the second screening group, at least A kind of transplantable tumor of mouse model has Cytogenetic Features t (11;19), and the transplantable tumor represent BCP-ALL, T-ALL or MLL hypotypes.

104. according to the system described in any one of embodiment 85-103, wherein in the second screening group, at least A kind of transplantable tumor of mouse model has Cytogenetic Features t (4;Or t (1 11);11), and the transplantable tumor represent BCP-ALL, T-ALL or MLL hypotypes.

105. the system described in any one of embodiment 60-104 is being used to prepare comment preclinical to drug candidate progress Purposes in the system estimated.

It is not intended to be limited by any theory, following embodiments is just for the sake of the device of explaination the application, method and is The working method of system, rather than limit the range of the present application.

Embodiment

The system of the structure assessment leukemia treating drug candidate of embodiment 1

It selects clinical signs and goes out the Patients With Acute Lymphoblastic Leukemia of chemotherapy drug resistance or the acute lymphoblastic of recurrence Chronic myeloid leukemia patient, collects the sample of bone marrow of the 2-4 milliliters of patients, and establishes the transplantable tumor mouse from these patients Model.Briefly, the sample of bone marrow from the leukaemic is prepared as cell suspension, and uses monocyte separation medium The cell suspension to be centrifuged.Then, it obtains the cellular layer comprising leukaemia cell and prepares leukaemia cell Suspension judges whether the leukaemia is T cell type leukaemia, and for non-T cell type leukaemia, removal is obtained described white T cell in blood disease cell suspension obtains leukaemia cell's suspension to be seeded, and keeps the leukaemia cell to be seeded outstanding The whole density of leukaemia cell is 2x10 in liquid⁷/ ml to 5x10⁷/ml.It is described white from what is obtained for T cell type leukaemia Blood disease cell suspension prepares leukaemia cell's suspension to be seeded, and the wherein whole density of leukaemia cell is 2x10⁷/ ml is extremely 5x10⁷/ml.Then, immune-deficient mice appropriate is selected according to the type of leukemia of the patient, and to described immune scarce Swaged mouse carries out radioactivity processing.Leukaemia cell's suspension injection inoculation that T cell is substantially free of described in being obtained arrives In the immune-deficient mice handled through radioactivity, and obtain the required transplantable tumor mouse mould from leukaemic Type.

The gene expression analysis of cytotoxicity experiment and full-length genome has been carried out to the transplantable tumor mouse model, it was demonstrated that Clinical correlation between constructed transplantable tumor mouse model and patient.The gene of full-length genome has been carried out to the mouse model Expression analysis and genome sequencing analysis, to which the acute lymphatic leukemia transplantable tumor for having chosen each required hypotype is small Mouse model.Member of therein ten kinds of mouse models as the first screening group is had chosen, and using the first screening group as standard Evaluation Platform carries out the drug screening of first stage.Ten kinds of transplantable tumor mouse models that the criterion evaluation platform includes (PDX) number be respectively ALL-2, ALL-4, ALL-7, ALL-17, ALL-19, ALL-8, ALL-16, ALL-31, ALL-3 and MLL-7, the transplantable tumor mouse model for representing BCP-ALL including 5 kinds, 3 kinds represent T cell acute lymphoblastic leukemia Transplantable tumor mouse model and 2 kinds of transplantable tumor mouse models for representing mixed lineage leukemia, embodiments information such as 1 institute of table Show:

Table 1

In addition, in addition having chosen 48 kinds of transplantable tumor mouse models as the second screening group, to carry out the drug of second stage Screening.The second screening group includes 12 kinds of transplantable tumor mouse models for representing BCP-ALL hypotypes, their PDX numbers point Not Wei ALL-11, ALL-25, ALL-50, ALL-51, ALL-52, ALL-53, ALL-54, ALL-55, ALL-56, ALL-57, ALL-58 and ALL-59.Further include the transplantable tumor mouse model of 12 kinds of T-ALL hypotypes, their PDX in the second screening group Number is respectively ALL-27, ALL-29, ALL-30, ALL-32, ALL-33, ALL-34, ALL-35, ALL-36, ALL-39, ALL- 42, ALL-43 and ALL-44.Further include the transplantable tumor mouse model of 7 kinds of MLL hypotypes, their PDX in the second screening group Number is respectively MLL-1, MLL-2, MLL-3, MLL-5, MLL-6, MLL-8 and MLL-14.Further include 6 in the second screening group The transplantable tumor mouse model of kind of ETP-ALL hypotypes, their PDX numbers are ETP-1, ETP-2, ETP-3, ETP-4, ETP-5 and ETP-6.In addition, further include 11 kinds of mouse models with the transplantable tumor comprising JAK gene mutations in the second screening group, it PDX numbers be ALL-10, Tgt-020, Tgt-038, Tgt-047, Tgt-052, Tgt-144, Tgt-174, Tgt-258, Tgt-084, Tgt-145 and Tgt-161.

Fig. 1 shows being controlled for assessing leukaemia for the transplantable tumor mouse composition of the first screening group and the second screening group The system for treating drug candidate.The characterization of the transplantable tumor of part mouse model in second screening group is summarised in table 2:

Table 2

Embodiment 2

Effect of drugs is commented with the system for the assessment leukemia treating drug candidate that structure obtains in embodiment 1 Estimate.The part drug candidate assessed is as shown in table 3.In addition, the drug candidate assessed further includes vincristine, ground plug rice Pine, cyclophosphamide, vincristine, dexamethasone and leunase combination, NSC750854, topotecan, Volasertib, Serdemetan, JNJ-26481585, KTP-330, ninopterin, adriamycin, left-handed asparagine, chlorine method Draw shore, Carfilzomib, tesirolimus, all-trans retinoic acid, SAHA and retinamide.

Table 3

Evaluation process is summarized as follows:When leukaemia cell reaches 1- in the peripheral blood of constructed transplantable tumor mouse model When 5%, which is grouped into vehicle control group and administration group at random, every group of 6 mouse, to the candidate medicine of mouse application Object.Administration time, dosage and administering mode corresponding to selected exemplary candidate drug and drug is as follows:

Vincristine:Intraperitoneal injection, 0.5mg/kg, once a week, it is for 4 weeks;

Ninopterin:Intraperitoneal injection, 5mg/kg, once a day, every other week injection continue 8 weeks;

Dexamethasone:Intraperitoneal injection, 15mg/kg, once a day, it is for 4 weeks;

Adriamycin:Intravenous injection, 1.5mg/kg, once a week, it is for 4 weeks;

Left-handed asparagine:Intraperitoneal injection, 1000KU/kg, once a day, it is for 4 weeks.

After applying drug candidate to the transplantable tumor mouse model, huCD45 is monitored weekly with flow cytometer⁺And/or CD19⁺The variation of cell proportion in the mouse peripheral blood cell, and by the small of the vehicle control group and administration group Mouse is compared, to understand effect of the drug candidate to leukemia treating.

In the present embodiment, the evaluation criteria for pharmaceutical efficacy is as shown in Fig. 2, leftmost curve part is the white blood of people in Fig. 2 Ratio of the sick cell during administration in mouse peripheral blood, right block are shown according to drug candidate to people's cell (huCD45⁺ And/or CD19⁺) ratio influence, drug is divided into six grades.Curve 1 indicates that progressive disease 1, curve 2 indicate progress Property disease 2, curve 3 indicate stability disease, curve 4 indicate part alleviate, curve 5 indicate complete incidence graph, curve 6 indicate continue Complete incidence graph.Only as leukaemia cell in drug kill Mice Body, and so that its ratio is kept below 1%, and maintain 2 weeks or more When, it is believed that the drug is to make disease complete incidence graph.Therefore, according to the standard of the application, only drug candidate reaches curve 5 and 6 Shown in standard when, be considered as just effective drug candidate.

After the above-mentioned first round screens, the assessment result to part drug candidate is as shown in figure 3, wherein effect 1-6 grades Grade scale it is identical as the standard that Fig. 2 is shown, filled black frame representative do not assess.

It is showing according to fig. 3 as a result, when certain drug candidate (such as vincristine, dexamethasone and leunase Joint dispenser) when showing effective to the transplantable tumor mouse model more than 80% in the first screening group, it can directly be recommended into Enter clinical test or further confirms that its effect in all or part of member of the second screening group.

When certain drug candidate (such as PR-104) shows the transplantable tumor mouse model of 50%-80% in the first screening group When effective, its effective sex ratio in the transplantable tumor mouse model for representing each leukaemia hypotype can determine whether.For example, drug candidate PR-104 all showing effectively 50% transplantable tumor mouse model in the first screening groups, but it is to 100% representative T- The transplantable tumor mouse model of ALL hypotypes is shown effectively, therefore, in the second wheel screening, is selected in the second screening group and is represented T-ALL 12 kinds of transplantable tumor mouse models of hypotype further test the validity that PR-104 is directed to the subdivision hypotype.The results are shown in Figure 4. As shown in Figure 4, drug candidate PR-104 has excellent effect in terms for the treatment of T-ALL.

In addition, when certain drug candidate (such as AZD1480) in the first screening group to 80% or less (such as 70% hereinafter, 60% hereinafter, 50% or less or less) transplantable tumor mouse model when show effective, if it is the medicine of certain specific target spot of targeting Object then selects to be positive transplantable tumor mouse model to the specific target spot from the second screening group, and selected The validity of the drug candidate is further assessed in transplantable tumor mouse model.For example, drug candidate Dasatinib (Dasatinib) To be directed to Ph+[t(9;22)]Targeted drug, although the first round screen in, the shifting in the first screening group only to 10% It plants tumor mouse model to show effectively, but may be selected to have in the second screening group and include Cytogenetic Features Ph+[t(9;22)]'s The mouse model of transplantable tumor does not have other comprising cytogenetics spy further to assess the validity of the drug candidate Levy Ph+[t(9;22)]Transplantable tumor mouse model as a contrast.In another example drug candidate AZD1480 is a kind of JAK1/2's Inhibitor predicts that its is only possible effective to the leukaemia hypotype containing JAK gene mutations.The first round screen in, only without The assessment of a small number of negative controls has been carried out in the transplantable tumor mouse model of JAK gene mutations, then in the second wheel screening, with Including further having evaluated the validity of drug candidate AZD1480 in the mouse model of the transplantable tumor of JAK gene mutations.However, The results show drug candidate is invalid, it is negated and enters clinical possibility, the results are shown in Figure 5 specific experiment.

Although being more than that 50 kinds of drug candidates are shown in vitro experiment through the present processes and system evaluation Validity, wherein only 20% drug candidate is (for example, Alisertib (MLN8237), Selumetinib, Talazoparib (BMN673), NTX-010, IGF-1R antibody and Eribulin) effective and quilt is assessed as in the present processes and system Recommend to enter clinical test.Therefore, the present processes and system greatly improve the efficiency and accuracy rate of Preclinical evaluation, And then be conducive to that suitable drug candidate is selected to carry out clinical test, to improve the success rate of clinical test.

Aforementioned detailed description is provided with way of example with explaining, scope of the appended claims are not intended to limit. A variety of variations of current embodiment cited herein are it will be apparent that and retaining for those of ordinary skills In the range of the attached claims and its equivalent program.

Claims

2) directly the drug candidate is recommended to enter clinical test as a result, determining according to the entry evaluation, or in the second sieve The validity of the drug candidate is further assessed in all or part of member of choosing group;

The wherein described first screening group and the second screening group include respectively that the transplantable tumor at least one leukaemic source is small The transplantable tumor of mouse model, each mouse model represents a kind of leukaemia hypotype;

The mouse model is humanized mouse model;And

Leukaemia hypotype in the second screening group representated by the transplantable tumor of mouse model includes all first screening groups Leukaemia hypotype representated by the transplantable tumor of middle mouse model.

2. according to the method described in claim 1, the wherein described leukaemia includes acute lymphoblastic leukemia.

3. according to the method described in any one of claim 1-2, wherein in the first screening group mouse model transplantable tumor Representative leukaemia hypotype includes selected from the group below one or more:B cell precursor cell Acute Lymphoblastic Leukemia (BCP-ALL), T cell acute lymphoblastic leukemia (T-ALL) and mixed lineage leukemia (MLL).

4. method according to any one of claim 1-3, wherein in the first screening group mouse model transplantable tumor With one or more in following Cytogenetic Features:

A) normal;

b)Ph+,t(9;22);

c)t(17;19);

d)[4]/46,XY[14];

e)t(11;19);With

f)t(4;11).

5. according to the described method of any one of claim 1-4, wherein in the second screening group mouse model transplantable tumor Representative leukaemia hypotype includes selected from the group below one or more:BCP-ALL, T-ALL, MLL and Pre-Tcell precursor are thin Born of the same parents' acute lymphoblastic leukemia (ETP-ALL).

6. a kind of system for assessing leukemia treating drug candidate, the system comprises the first screening groups and second to screen Group, wherein:

The first screening group and the second screening group respectively include the transplantable tumor mouse mould at least one leukaemic source Type,

The transplantable tumor of each mouse model represents a kind of leukaemia hypotype;

The mouse model is humanized mouse model;And

7. system according to claim 6, wherein the leukaemia includes acute lymphoblastic leukemia.

8. according to the system described in any one of claim 6-7, wherein in the first screening group mouse model transplantable tumor Representative leukaemia hypotype includes selected from the group below one or more:B cell precursor cell Acute Lymphoblastic Leukemia (BCP-ALL), T cell acute lymphoblastic leukemia (T-ALL) and mixed lineage leukemia (MLL).

9. according to the system described in any one of claim 6-8, wherein in the first screening group mouse model transplantable tumor With one or more in following Cytogenetic Features:

A) normal;

b)Ph+,t(9;22);

c)t(17;19);

d)[4]/46,XY[14];

e)t(11;19);With

f)t(4;11).

10. according to the system described in any one of claim 6-9, wherein in the second screening group mouse model transplantable tumor Representative leukaemia hypotype includes selected from the group below one or more:BCP-ALL, T-ALL, MLL and Pre-Tcell precursor are thin Born of the same parents' acute lymphoblastic leukemia (ETP-ALL).