EP0975758A1 - POLYPEPTIDE A ACTIVITE REGULATRICE DE LA GTPase, ACIDES NUCLEIQUES CODANT CE POLYPEPTIDE ET UTILISATION DE CES ACIDES ET POLYPEPTIDE DANS DES DIAGNOSTICS ET THERAPIES - Google Patents

POLYPEPTIDE A ACTIVITE REGULATRICE DE LA GTPase, ACIDES NUCLEIQUES CODANT CE POLYPEPTIDE ET UTILISATION DE CES ACIDES ET POLYPEPTIDE DANS DES DIAGNOSTICS ET THERAPIES

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Publication number
EP0975758A1
EP0975758A1 EP98946325A EP98946325A EP0975758A1 EP 0975758 A1 EP0975758 A1 EP 0975758A1 EP 98946325 A EP98946325 A EP 98946325A EP 98946325 A EP98946325 A EP 98946325A EP 0975758 A1 EP0975758 A1 EP 0975758A1
Authority
EP
European Patent Office
Prior art keywords
sequence
polynucleotide
polypeptide
gene
graf
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98946325A
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German (de)
English (en)
Inventor
Fritz Professor Dr. Lampert
Arndt Dr. Borkhardt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BORKHARDT, ARNDT, DR.
LAMPERT, FRITZ, PROFESSOR DR.
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to EP98946325A priority Critical patent/EP0975758A1/fr
Publication of EP0975758A1 publication Critical patent/EP0975758A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity
    • C07K14/4705—Regulators; Modulating activity stimulating, promoting or activating activity
    • C07K14/4706—Guanosine triphosphatase activating protein, GAP
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention discloses polypeptides and polynucleotides derived from a human gene which has antiproliferative and tumor suppressor properties and the use thereof in diagnostics and therapy of cancer, in particular of myelodysplastic syndromes and acute yeloid leukemias .
  • the antiproliferative property is of importance in diagnostics and therapy of cardiac hypertrophy, heart failure and congenital heart defects .
  • Chromosome abnormalities associated with hematologic malignancies alter the normal structure and function of genes that control cell proliferation and differentiation either in a positive or negative fashion.
  • Normal cell division is positively regulated or activated through signal transduction pathways composed of extracellular signals, receptor G proteins, protein kinases and transcription factors.
  • the genes encoding such proteins are also known as proto-oncogenes , because mutations turn them into dominant oncogenes with altered properties.
  • proto-oncogenes are frequently affected by chromosome translocations .
  • fusion of the participating genes leads to either abnormal activation or to the generation of novel chimeric oncogenes with new functions .
  • MLL mixed-lineage leukemia
  • Chromosomal abnormalities associated with distinct subsets of human leukemia suggest a link between specific genetic alterations and clinical outcome.
  • a tide correlation between the cytogenic anomaly and the progression of the disease indicates a direct cause and effect relationship between the genotype and the disease phenotype.
  • Acquired interstitial loss of the long arm of chromosome 5 ( 5q-chromosome) is seen in patients with a range of myeloid disorders.
  • a certain region in the long arm of chromosome 5 is consistently deleted in most of these patients suggesting that physical loss of an important gene from the 5q-chr ⁇ mosome coupled with a mutation of the second allele on the remaining "normal" chromosome 5 results in total inactivation of this key regulatory gene.
  • the different regions of the chromosome affected by the deletions can be designated by the commonly used nomenclature.
  • the designation 5q31 for example means that the long arm (q) of chromosome 5 (5) is affected.
  • the long arm of chromosome 5 is divided in three main areas (3; first digit) whereby said areas are further subdivided into five areas (second digit; here area 1 ) .
  • the products of many so-called tumor suppressor genes inhibit the same signal transduction pathway and are negative regulators of the cell cycle. Since mutations in these genes act recessively and result in a loss of function, uncontrolled cell growth takes place only after inactivation or elimination of both alleles. Most often, one allele is deleted, whereas the second one may be functionally compromised by various other mutations.
  • MDS myelodysplastic syndromes
  • AML acute myeloid leukemias
  • JCMML juvenile chronic myelomonocytic leukemia
  • Integrin-mediated cell adhesion to the extracellular matrix has both structural and biochemical ramifications for cell homeostasis . Integrins bind components of the ECM via large extracellular domains. The sites of integrin-ECM interaction trigger the formation of protein complexes on the cytoplasmic face of the plasma membrane termed focal adhesions. Focal adhesions contain several proteins with the capacity to simultaneously bind the short cytoplasmic tails of integrin and actin filaments. Thus, focal adhesions serve to anchor the actin cytoskeleton to the plasma membrane and directly link the extracellular and intracellular environments. Besides playing a structural role, the binding of integrins to ECM results in the initiation of intracellular signaling cascades.
  • FAK focal adhesion kinase
  • the Graf gene encodes a regulator of the Rho family of small GTPases that binds to a tyrosine kinase.
  • the Rho family belongs to the RAS superfamily and consists of five distinct types of GTP-binding proteins: RhoA, B & C; Racl & 2; Cdc42 & G25K; TC10 and RhoG, respectively.
  • Rho, Rac and Cdc42 regulate the organization of the actin cytoskeleton. They control the assembly of actin stress fibers and focal adhesion complexes which anchor the actin cytoskeleton to the plasma membrane in normal cells, including neutrophils, lymphocytes, as well as platelets.
  • the Graf protein of the present invention binds to the C-terminal domain of ppl25 FAK , one of the tyrosine kinases predicted to be a critical component of the integrin signaling transduction pathway, in a SH3 domain-dependent manner and may thus preferentially stimulate the GTPase activity of the GTP- binding proteins RhoA and Cdc42. Amongst several other effects, this might initiate intracellular signaling cascades that participate in gene expression, cell survival, cell migration and adhesion, and differentiation.
  • Rho family GTPases also play a role in the regulation of growth control, because each of the three GTPases Rho, Rac and Cdc42 can induce Swiss 3T3 cells to progress through Gl and to enter the S phase of the cell cycle.
  • inhibitors of Rho, Rac and Cdc42 block serum induced DNA synthesis .
  • the notion that Graf may have pleiotropic effects on integrin-mediated cell signaling is further corroborated by its presence in a variety of tissues, with a particular abundant expression in avian embryonic brain and liver and, as found in the course of the present invention, in human heart, brain and placenta.
  • Rho and Cdc42 must have important roles in the development of human tumors, because many regulators of Rho have oncogenic activity.
  • the mitigation or elimination of the negative regulatory function of the Graf might permanently activate Rho and Cdc42.
  • Such a disturbance could significantly contribute to many neoplastic features, including factor and anchorage independent growth, invasion and metastasis.
  • a biallelic loss or inactivation of Graf could thus be one of the molecular switches initiating neoplastic transformation in hematologic neoplasms with a del(5q).
  • the Graf gene is the second GAP-encoding gene involved in a leukemia-associated chromosomal translocation.
  • the only other one currently known is the highly homologous BCR gene at chromosome 22qll which is fused to the ABL gene in chronic myeloid and acute lymphoblastic leukemias harboring a t ( 9 ; 22 ) (q34 ;qll ) .
  • the functionally important GAP domain is lost in both the predicted hybrid proteins BCR/ABL and MLL/Graf. Whether the partial homology to the bombesin-like family members is functionally important remains open.
  • the bombesins are bio- active peptides that were originally isolated from amphibian skin.
  • Bombesin-like immunoreactivity is found at high concentrations in fetal and neonatal lung, but nearly absent in adult lung tissue.
  • lung cancer cell lines and human tumors seem to contain much higher levels of BLI .
  • Graf is also highly expressed in an adenocarcinoma cell line of the lung, but absent in normal lung tissue.
  • polypeptides of the present invention are derived from a human gene it should be noted that also such derivatives are biologically active which differs somewhat from the amino acid sequence as given above.
  • the present invention comprises therefore also such fragments of the polypeptides which have at least a partial sequence derived from the disclosed amino sequence whereby said partial fragment comprises preferably more than 100, more preferably more than 120 and most preferably more than 150 consecutive amino acids of the above given sequence.
  • the underlined regions are especially preferred .
  • the protein of the present invention is a rather large protein having more than 700 amino acids.
  • the present invention concerns also proteins which have a slightly modified amino acid sequence. It is, however, essential that the biological activity is maintained. The person skilled in the art knows that in some areas which are essential for biological activity no changes are allowed. On the other hand in regions which are not extremely important for biological activity major changes in the amino acid sequence may be tolerated.
  • the present invention covers also such polypeptides which are highly homologous to Seq. ID-No. 1. Preferably the homology is at least 90% and more preferably more than 95% based on the amino acid sequence .
  • the polypeptide of the present invention which is called "Graf" is a GTPase regulator associated with focal adhesion kinase and most likely a GTPase-activating protein.
  • the polypeptide of the present invention can be used in a pharmaceutical composition comprising such a polypeptide.
  • the pharmaceutical composition of the present invention can be used for the treatment of cancer, whereby the pharmaceutical composition is preferably formulated for parenteral application. It has been found in the course of the present invention that pharmaceutical compositions of the present invention comprising the polypeptide of the present invention or a fragment thereof may be also used for the treatment of cardiovascular diseases .
  • cardiovascular disease includes especially congenital heart defects and heart failure.
  • Another aspect of the present invention concerns polynucleotides coding for said Graf gene comprising the nucleotide sequence as shown in Figure 2 (Seq.ID-Nr. 2) or a partial sequence thereof having at least 15 consecutive nucleotides .
  • a partial sequence of the nucleotide sequence given above has preferably at least 25 consecutive nucleotides and more preferably at least 50 consecutive nucleotides. It should be stressed that the present invention covers two groups of polynucleotides. One group concerns rather short polynucleotides which may be used as a diagnostic tool for nucleic acid amplification. The amplification of partial sequences by polymerase chain reaction (PCR) or similar techniques like NASBA are well-known to the person skilled in the art. It is therefore an object of the present invention to use short polynucleotides having between about 10 and about 25 nucleotides as primers. Slightly longer polynucleotides may be used as probes.
  • PCR polymerase chain reaction
  • Probes have regularly about 20 to about 40 nucleotides as a short sequence of consecutive nucleotides of Figure 2.
  • the present invention concerns therefore short sequences of consecutive nucleotides having between about 10 to about 50 nucleotides whereby the length of the polynucleotides depends on the function of the nucleotide as primer and/or probe.
  • the present invention covers also longer polynucleotides which may be used for the production of the gene product.
  • the longer polynucleotides code for the polypeptide of the present invention.
  • the invention covers also variations of this polynucleotide whereby the variations have a rather high homology to the claimed polynucleotides.
  • a homology of 90% means that 90 nucleotides out of 100 consecutive nucleotides are identical. Consequently the present invention concerns therefore longer polynucleotides whereby longer means at least 500 nucleotides, preferably more than 1000 nucleotides which have a rather high homology.
  • the preferred polynucleotides have a homology of at last 80%, preferably of at least 90% and most preferably of about 95%.
  • the polynucleotides have a nucleotide sequence or a partial nucleotide sequence of the sequence given in Figure 2.
  • the polynucleotides of the present invention comprise preferably also sequences which are required in order to allow the polynucleotide to replicate in a host cell. Those sequences are well-known in the art and are essential for a vector in order to replicate in a host cell.
  • the vectors of the present invention are preferably a plasmid or a viral vector comprising a polynucleotide of the present invention. Such a vector is used in order to transform a suitable host cell in order to cause said host cell to express a polypeptide according to the present invention.
  • the promotor region coding for the polypeptide of the present invention has been sequenced and further characterized. It is therefore also an object of the present invention to use the promotor region of the Graf gene for therapy. Either the promotor region may be used directly in therapy, for example in vectors suitable for gene therapy or suitable antisense sequence which interfere with the promotor region may also be used.
  • testkits may comprise suitable primer polynucleotides and/or probe polynucleotides .
  • Those testkits may also be based on methylation-specific PCR or Southern hybridization approaches using methylation-sensitive restriction enzymes.
  • testkits for the diagnosis of chromosomal aberrations by hybridization of nucleic acids.
  • Said testkits comprise at least a polynucleotide of the present invention.
  • Those testkits are preferably testkits for performing a Southern Blot hybridization or for performing a polymerase chain reaction. Beside the polynucleotides of the present invention such kits comprise frequently used components which are well-known to the person skilled in the art.
  • Those testkits may also be designed for hybridization procedures in connection with "microchip arrays". Such computer-assisted arrays are well-known to persons skilled in the art.
  • a polypeptide in another aspect of the present invention can be used for the preparation of antibodies or functional fragments of antibodies like Fab- or F v -fragments .
  • the technique of producing antibodies or monoclonal antibodies is well-known to an average person skilled in the art.
  • the present invention is further illustrated by the following examples .
  • Cytogenetic analysis of a bone marrow sample obtained from a child with JCMML revealed a unique translocation t ( 5 ; 11 ) ( q31 ;q23 ) .
  • Southern-blot analysis and fluorescence in situ hybridization (FISH) subsequently confirmed that this translocation disrupted the MLL gene. This enabled the isolation of the fusion partner with a 5' and 3' rapid amplification of cDNA ends polymerase chain reaction (RACE RT- PCR) technique.
  • RACE RT- PCR polymerase chain reaction
  • GAP guanosine triphosphatase activating
  • SH3 domain amino acids 683 to 734
  • MLL the break occurred after exon 7 and in the Graf gene at nucleotide numbers 1629/30.
  • Exon 6 of the MLL gene is deleted in the MLL/ Graf hybrid mRNA.
  • the predicted fusion protein consists of the N-terminal part of MLL and the C-terminal part of Graf . It retains the putative "AT-hook" DNA binding domain and the DNA methyltransferase motifs present in the MLL amino-terminal region, and the SH3 domain of the Graf gene, whereas the GAP domain of Graf is deleted.
  • RT-PCR revealed that the fusion mRNA of the MLL/Graf but not that of the reciprocal Graf /MLL is expressed.
  • an approximately 13 kb fragment of the MLL/Graf sequence on the genomic DNA level in the case with the t(5;ll), but in none of four leukemic cell lines and 3 healthy individuals could be amplified.
  • G1/G3 and G2/G4 that are positioned at nucleotide numbers 1559-1591 (Gl), 1736-1608 (G3), 1593-1625 (G2) and 1674-1645 (G4), respectively, we amplified an approximately 11 kb long intron of the Graf gene in which the break and fusion with MLL had taken place.
  • High molecular weight DNA was isolated according to standard pocedures . Aliquots of 5 ⁇ g DNA were digested with Hind III restriction endonuclease (Boehringer Mannheim, Germany). The DNA was separated by electrophoresis in a 0,7 % agarose gel at 25 V over night and hybridized onto nylon membranes. The blots were probed with a cDNA clone of the human Graf gene ranging from nucleotide 225 to 1392. The cDNA probe was labelled by incorporating digoxigenine 11-dUTP.
  • the 5 ' -genomic region of the human Graf gene has been cloned by a commercially available "Genome walker” kit following the instructions of the manufacturer (Clontech, Palo Alto, USA). We recovered a 1482 bp nucleotide sequence which was subsequently used for further studies.
  • the nucleic acid sequence of the promotor is given in Figure 4.
  • the 1482 bp sequence has been cloned in a pGL vector containing the firefly luciferase downstream of the respective promotor sequence.
  • the luciferase activity was measured with the help of a Beckmann luminometer .
  • the Renilla luciferase gene was coupled to the constitutive SV40 early enhancer/promotor region that provides strong, constitutive expression of the Renilla luciferase in a variety of cell types.
  • the identified Graf promotor region leads to a 1.5 times higher luciferase activity.
  • the methylation-specific PCR was carried out at 65°C annealing temperature for 35 cycles (hot-start procedure) .
  • the amplicons were analyzed by agarose gel analysis and positive results were verified by genomic DNA sequencing.
  • Methylation of the Graf promotor sequence was found in two out of the ten patients (patients no. 6 and 8 of Table 1). This finding clearly indicates that aberrant methylation of the Graf gene promotor occurs in patients with leukemia and chromosomal deletion at 5q.

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Abstract

L'invention concerne un polypeptide régulateur de la GTPase, associé à une kinase d'adhésion focale et renfermant la séquence d'acides aminés (I).
EP98946325A 1997-08-14 1998-08-13 POLYPEPTIDE A ACTIVITE REGULATRICE DE LA GTPase, ACIDES NUCLEIQUES CODANT CE POLYPEPTIDE ET UTILISATION DE CES ACIDES ET POLYPEPTIDE DANS DES DIAGNOSTICS ET THERAPIES Withdrawn EP0975758A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP98946325A EP0975758A1 (fr) 1997-08-14 1998-08-13 POLYPEPTIDE A ACTIVITE REGULATRICE DE LA GTPase, ACIDES NUCLEIQUES CODANT CE POLYPEPTIDE ET UTILISATION DE CES ACIDES ET POLYPEPTIDE DANS DES DIAGNOSTICS ET THERAPIES

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP97114112A EP0897001A1 (fr) 1997-08-14 1997-08-14 Polypeptide à l'activité régulatrice de GTPase, les acides nucléiques correspondants ainsi que leurs emplois diagnostiques et thérapeutiques
EP97114112 1997-08-14
EP98946325A EP0975758A1 (fr) 1997-08-14 1998-08-13 POLYPEPTIDE A ACTIVITE REGULATRICE DE LA GTPase, ACIDES NUCLEIQUES CODANT CE POLYPEPTIDE ET UTILISATION DE CES ACIDES ET POLYPEPTIDE DANS DES DIAGNOSTICS ET THERAPIES
PCT/EP1998/005143 WO1999009157A1 (fr) 1997-08-14 1998-08-13 POLYPEPTIDE A ACTIVITE REGULATRICE DE LA GTPase, ACIDES NUCLEIQUES CODANT CE POLYPEPTIDE ET UTILISATION DE CES ACIDES ET POLYPEPTIDE DANS DES DIAGNOSTICS ET THERAPIES

Publications (1)

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EP0975758A1 true EP0975758A1 (fr) 2000-02-02

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Family Applications (2)

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EP97114112A Withdrawn EP0897001A1 (fr) 1997-08-14 1997-08-14 Polypeptide à l'activité régulatrice de GTPase, les acides nucléiques correspondants ainsi que leurs emplois diagnostiques et thérapeutiques
EP98946325A Withdrawn EP0975758A1 (fr) 1997-08-14 1998-08-13 POLYPEPTIDE A ACTIVITE REGULATRICE DE LA GTPase, ACIDES NUCLEIQUES CODANT CE POLYPEPTIDE ET UTILISATION DE CES ACIDES ET POLYPEPTIDE DANS DES DIAGNOSTICS ET THERAPIES

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP97114112A Withdrawn EP0897001A1 (fr) 1997-08-14 1997-08-14 Polypeptide à l'activité régulatrice de GTPase, les acides nucléiques correspondants ainsi que leurs emplois diagnostiques et thérapeutiques

Country Status (5)

Country Link
EP (2) EP0897001A1 (fr)
JP (1) JP2002503441A (fr)
AU (1) AU754925B2 (fr)
CA (1) CA2300805A1 (fr)
WO (1) WO1999009157A1 (fr)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9909157A1 *

Also Published As

Publication number Publication date
AU754925B2 (en) 2002-11-28
CA2300805A1 (fr) 1999-02-25
EP0897001A1 (fr) 1999-02-17
JP2002503441A (ja) 2002-02-05
AU9341898A (en) 1999-03-08
WO1999009157A1 (fr) 1999-02-25

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