WO1991015116A1 - Animaux doublement transgeniques - Google Patents

Animaux doublement transgeniques Download PDF

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Publication number
WO1991015116A1
WO1991015116A1 PCT/AU1991/000116 AU9100116W WO9115116A1 WO 1991015116 A1 WO1991015116 A1 WO 1991015116A1 AU 9100116 W AU9100116 W AU 9100116W WO 9115116 A1 WO9115116 A1 WO 9115116A1
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cells
animal
transgenic
bcl
transgenic animal
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PCT/AU1991/000116
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English (en)
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Suzanne Cory
Andreas Strasser
Jerry Adams
Alan Harris
Mary L. Bath
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Amrad Corporation Limited
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A01K67/0275—Genetically modified vertebrates, e.g. transgenic
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/82—Translation products from oncogenes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/02—Animal zootechnically ameliorated
    • A01K2267/025—Animal producing cells or organs for transplantation
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/0331—Animal model for proliferative diseases
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/035—Animal model for multifactorial diseases
    • A01K2267/0381—Animal model for diseases of the hematopoietic system

Definitions

  • the present invention relates generally to a transgenic non-human animal and in particular to a doubly transgenic non-human animal carrying oncogenes which result in a predisposition of the transgenic animal to form novel lymphoblastic tumour cells.
  • U.S. Patent No. 4,736,866 in the name of the President and Fellows of Harvard College discloses a transgenic non-human animal, and in particular a mouse, whose germ cells and somatic cells contain an activated oncogene sequence such as a coding sequence of a c-myc gene introduced into the animals, or an ancestor of the animal, at an embryonic stage.
  • mice produced by oocyte injection and harbouring the murine c-mvc oncogene under the control of the murine immunoglobulin heavy chain enhancer [E ⁇ ] are known and well characterised (Harris et al.. J. Exp. Med. 167: 353, 1988).
  • the oncogene bcl-2 was discovered by virtue of its linkage to the immunoglobulin heavy chain (IgH) locus in the 14:18 translocation typical of human follicular lymphoma.
  • the 24 kd cytoplasmic protein encoded by bcl-2 is not affected by the translocation, but its expression is rendered constitutive, probably because of the influence of the cis-linked, albeit distant, IgH enhancer.
  • bcl-2 may represent a new class of gene that promotes cell survival rather than proliferation. Consistent with this hypothesis, transgenic mice produced by oocyte injection and harbouring the bcl-2 gene under the control of IgH enhancer [E ⁇ ] display a several fold expansion of the B lymphoid compartment and extended survival of these cells in tissue culture (Strasser et al. , manuscript in preparation). E ⁇ -bcl-2 mice do not display marked susceptibility to tumour development, unlike E ⁇ -c-mvc mice which all succumb to either pre-B or B lymphoma (Adams et al. Nature 318: 533-538, 1985).
  • one aspect of the present invention relates to a doubly transgenic non-human animal containing and expressing two oncogenic sequences introduced into the germ cells or haemopoietic stem cells of said animal or an ancestor of said animal, resulting in said animal producing lymphoblastic tumour cells characterised in that the cells are large and negative for expression of both immunoglobulin (Ig) and the pre-B marker PB76 but express high levels of CD45R [B220] , CD4 and Sca-1 and low levels of Thy-1.
  • Ig immunoglobulin
  • PB76 pre-B marker
  • the doubly transgenic animals of the present invention can be used as tester animals to screen for anti-cancer agents and as a source of cells to screen for growth factors capable of supporting their growth in culture.
  • the haemopoietic cells of doubly transgenic animals of the present invention express two oncogene sequences resulting in the production of a novel type of lymphoblastic tumour cell.
  • the oncogene sequences which to date are the most effective in giving rise to this phenomenon are bcl-2 and c-mvc.
  • the present invention is directed to a doubly transgenic bcl-2/c-myc animal wherein the genes were originally introduced by oocyte injection and the animal is preferably a mammal and most preferably a rodent such as a mouse.
  • the present invention also extends to doubly transgenic animals produced by other means, for example, retrovirua infection of haemopoietic stem cells and using other oncogenic sequences and which result in animals producing lymphoblastic tumour cells characterised in that the cells are large and negative for expression of both Ig and the pre-B marker PB76 but express high levels of CD45R [B220] * , CD4 and Sca-1 and low levels of Thy-1.
  • the animal is a mammal and is most preferabl a rodent such as a mouse although the present invention is not so limited.
  • oncogene sequences which may be useful in the practice of the present invention include, but are not limited to, (using the standard notation) src, yes, fps, abl, ros, fgr, erbA, erbB, fms, mos, raf, Ha-ras, Ki-ras, N-ras, myb, fos, ski, rel, N-myc, ets, EIA, Itk, hck, neu, fyn.
  • src yes, fps, abl, ros, fgr, erbA, erbB, fms, mos, raf, Ha-ras, Ki-ras, N-ras, myb, fos, ski, rel, N-myc, ets, EIA, Itk, hck, neu, fyn.
  • the oncogene sequences used in accordance with the present invention may be separately or independently regulated. Expression may be constitutive or inducible. Preferably, the same regulatory sequence is used. Most preferably, the oncogenic sequences are under the contro of the IgH enhancer, E ⁇ .
  • another aspect of the present invention relates to a novel type of lymphoblastic tumour cell produced by the doubly transgenic bcl-2/c-myc animals described above, and which is characterised in that the cell is large and negative for expression of both Ig and the pre-B marker PB 76, , but expresses high levels of CD45R [B220] + , CD4 and Sca-1 and low levels of Thy-1.
  • pre-B and B cells in the bcl-2/c-myc mice do not appear to be fully transformed, despite their conspicuous over-production.
  • No pre-B or B-lymphomas were ever obtained on transplantation of either spleen or bone marrow populations where they predominated.
  • culturing these cell suspensions in vitro failed to result in rapid outgrowth of cells. Instead, the cultures remained relatively static for several weeks, whereupon clonal pre-B or B cell lines emerged, presumably as a result of the acquisition of additional mutation(s).
  • Constitutive bcl-2 and c-myc expression therefore apparently does not suffice to transform pre-B or B cells.
  • tumour cells were, in contrast, highly tumourigenic.
  • cell suspensions prepared from either thymus, lymph node, marrow or spleen produced tumours in syngeneic recipients within 26 to 67 days and, without exception, the tumour cells were large and expressed high levels of B220, CD4 and Sca-1 as well as low levels of Thy-1, but no detectable Ig, Mac-1, CD8 or PB76 (see Table 2).
  • the tumour cells also expressed high levels of class I and class II histocompatibility antigens but were negative for CD3, T cell receptor (TcR) ⁇ / ⁇ , BP-1, Mac-2 and Mac-3. They displayed no evidence of rearrangement of the IgH and the ⁇ and ⁇ TcR loci. These characteristics are those expected of cells very early in the haemopoietic lineage.
  • mice injected with cells from the 10 day old mouse died with tumours of CD4 + B220" cells. No pre- neoplastic expansion of the abnormal cell type was detectable.
  • bcl-2/c-mvc synergy in the doubly transgenic animals of the present invention has provided a novel cell type. It may not be a multipotential'haemopoietic stem cell with long term repopulating capacity, since this is currently believed to be Thy-l low , Sca-1 + , Mac-1 " , CD4 " , CD8 " and B220 " (Spangrude, Heimfeld and Weissman, Science 241: 58-62, 1988). However, one type of stem cell, the CFU-S, has now been shown to be CD4 low (Fredrickson & Basch J. Exp. Med. 169: 1473-1478, 1989).
  • the cells may well represent a transformed lymphoid. stem or progenitor cell.
  • the earliest known intrathymic T cell precursor has recently been characterised as Thy low , CD4 low , Sca-1 * but CD45R (B220)- (Wu et al.. Nature 349: 71-74, 1991).
  • the tumour cells produced in accordance with the present invention retain their growth factor requirements in vitro and thus provide means for assaying growth factors required for early haemo- or lympho- poiesis.
  • another aspect of the present invention comprises a method for detecting one or more growth factors required for the growth and/or differentiation ⁇ n vitro of the lymphoblastic tumour cells broadly described above.
  • the lymphoblastic tumour cells would be cultured in vitro in the presence of any source of such growth factors and the survival or death of said cells would indicate the respective presence or absence of growth factor(s) in said sample upon which the cells are dependent.
  • the source of growth factor could be a culture supernatant or a homogenous preparation of one or more molecules such as haemopoietic growth factors.
  • Another aspect of the present invention provides novel growth factor(s) on which the tumour cells broadly described above, or their normal untransformed counterpart, are dependent and which will allow said cells to grow in vitro and which can be distinguished from known haemopoietic growth factors including IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, CSF-1, M-CSF, GM-CSF, G-CSF, LIF and SCF, which do not support in vitro culture of the said cells.
  • the novel growth factor(s) may require the presence of one or several known growth factors in order to support the lymphoblastic tumour cells or their normal (non- neoplastic) counterpart.
  • Example sets out in detail the production of E ⁇ -c-myc/E ⁇ -bcl-2 mice, in accordance with the present invention, and the procedures for obtaining and culturing tumour cells therefrom.
  • EXAMPLE 1 E ⁇ -c-myc The strain used to mate with E ⁇ -bcl-2 mice was the well characterised E ⁇ -c-myc 292-1 (Adams et al.. Nature 318: 533-538, 1985; Harris et al.. J. Exp. Med. 167: 353-371, 1988) which express the murine c-myc gene under the control of the murine immunoglobulin heavy chain enhancer [E ⁇ ] .
  • the strain used to mate with E ⁇ -c-myc mice was the recently characterised Eu-bcl-2-22 strain (Strasser et al. , manuscript in preparation).
  • the transgene was constructed using vector pE ⁇ SV (Rosenbaum et al.. EMBO J. 8: 749-755, 1989). Briefly, a blunted EcoRI-Ta ⁇ l fragment of the bcl2 cDNA encoding residues 1-939 of the clone isolated by Cleary, Smith and Sklar Cell 47: 19-28, 1986) was cloned into the Smal site in the polylinker of the pE ⁇ SV vector.
  • the construct was digested with NotI endonuclease and the transgene separated from plasmid sequences as earlier described (Rosenbaum et al. , Supra). Transgenic mice were than produced essentially as described by Brinster et al. Proc. Natl. Acad. Sci. USA. 82: 4438-4442, 1985. Single cell fertilised eggs were obtained from superovulated C57BL/6 WEHI x SJL/J WEHI F j ⁇ hybrid [BSJFI] females mated with BSJFI males. Eggs that survived pronuclear injection with the E ⁇ -bcl-2 construct and cleaved during overnight culture were transferred to the oviduct of pseudopregnant females.
  • Transgenic mice were identified by dot-blot hybridisation of tail DNA to a 32 P-labelled fragment spanning the terminal SV40 sequence of the transgene. Each primary transgenic mouse was an F2 animal. Several independent strains were established from 1° mice by mating with non-transgenic BSJFI mice and designated E ⁇ -bcl-2-22, -25, etc.
  • mice from the E ⁇ -bcl-2-22 strain were mated with animals of the E ⁇ -c-myc 292-1 transgenic line. Doubly transgenic progeny were identified by virtue of the hybridisation of their tail DNA to both the SV40 probe and a pUC12 plasmid probe, which detects sequences present in the E ⁇ -myc transgene (Adams et al.. Supra.).
  • Mice were monitored at least weekly after weaning for tumour development by palpation of spleen and inguinal lymph nodes. Animals with overt tumours were sacrificed and cells dispersed mechanically from tumour tissue for flow cytometric analysis of immunofluorescence using established procedures (see Langdon et al.. Cell 47: 11, 1986). The tumours were transplanted into syngeneic (BSJFI) mice by intraperitoneal, intravenous or subcutaneous injection of 10 6 to 10 7 tumour cells. An analysis of the tumour cells is shown in Table 1 (see also Example 2).
  • Tumour cells are resuspended at 0.5 to 10 x 10 6 /ml in Dulbecco's Modified Eagle's Medium (DMEM) containing 5 x 10 "5 M 2-mercaptoethanol and 10% v/v foetal calf serum (FCS) or Iscove's medium + 10% v/v FCS containing maximal concentrations of a variety of known purified haemopoietic growth factors, either alone or in various combinations. Those tested include IL-1, IL-2, IL-3, IL- 4, IL-5, IL-6, IL-7, IL-9, IL-10, M-CSF, GM-CSF, G-CSF, LIF, SCF and CSF-1 and various combinations thereof.
  • DMEM Dulbecco's Modified Eagle's Medium
  • FCS 10% v/v foetal calf serum
  • FCS Iscove's medium + 10% v/v FCS containing maximal concentrations of a variety of known purified
  • B22CT cells comprised >90% of all bone marrow, spleen and lymph node cells "80% of thymus cells.
  • the numbers shown are the mean proportions ( ⁇ s.d.) of CD45R (B220) * cells from 4 terminally ill mice that stained with fluorochrome-labelled monoclonal antibodies specific for each of the other indicated cell surface molecules. Quantitation was by dual-fluorescence flow cytometry on a FACScan flow cytometer (Becton-Dickinson) .
  • tumour cells produced by the bcl-2Vc-myc doubly transgenic animals of the present invention were subject to further analysis by immunofluorescence, FACS analysis and ligand binding using established procedures. The results are shown in Table 2.
  • tumour cell is a neoplastic counterpart of a relatively early haemopoietic stem cell. This hypothesis is supported by the fact that these tumours retain their Ig and Tcr ⁇ and ⁇ genes in germline configuration.
  • CD45R [B220][general Thy 1[T cell and Ig[B cell hallmark] B-cell lineage marker] CFU-s marker] CD-3[T cell antigen]
  • CD4 [T cell and Ly-l[T cell marker]
  • CD-8 [T cell antigen] haemopoietic]
  • Gr-1 [granulocyte Tcr ⁇ / ⁇ [T cell CFU-s marker] marker] antigen receptor]
  • LIF receptor BP-1/6C3 [Leukaemia Inhibitory Factor receptor] F4/80[myeloid marker]
  • tumour cells An analysis of the tumour cells by Northern blotting showed that the cells were positive or negative for expression of markers shown in Table 3.

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Abstract

L'invention se rapporte, en général, à un animal transgénique non humain et, en particulier, à un animal non humain doublement transgénique porteur d'oncogènes, ce qui provoque sa prédisposition à former de nouvelles cellules tumorales lymphoblastiques.
PCT/AU1991/000116 1990-03-30 1991-03-28 Animaux doublement transgeniques WO1991015116A1 (fr)

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AUPJ9389 1990-03-30
AUPJ938990 1990-03-30

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023533A1 (fr) * 1992-05-08 1993-11-25 Exemplar Corporation Test in vivo de medicaments anti-neoplasiques
WO1996014401A1 (fr) * 1994-11-03 1996-05-17 Bradley Michael John Stringer Organismes transgeniques et leurs utilisations
WO2004001367A2 (fr) * 2002-06-24 2003-12-31 MedInnova Gesellschaft für medizinische Innovationen aus akademischer Forschung mbH Systeme de test destine a la detection de maladies cancereuses
EP2011866A1 (fr) * 2007-07-02 2009-01-07 Ludwig Boltzmann Gesellschaft GmbH Procédé de génération d'un animal non humain avec un oncogène

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2900389A (en) * 1987-12-15 1989-07-19 Trustees Of Princeton University, The Transgenic testing systems for mutagens and carcinogens
EP0169672B1 (fr) * 1984-06-22 1992-05-13 The President And Fellows Of Harvard College Méthode pour la production d'animaux transgéniques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0169672B1 (fr) * 1984-06-22 1992-05-13 The President And Fellows Of Harvard College Méthode pour la production d'animaux transgéniques
AU2900389A (en) * 1987-12-15 1989-07-19 Trustees Of Princeton University, The Transgenic testing systems for mutagens and carcinogens

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 113, No. 25, issued December 1990, (Columbus, Ohio, USA), T. MOROY et al., "1gH Enhancer Deregulated Expression of L-Myc Abnormal T Lymphocyte Development and T Cell Lymphomagenesis"; & EMBO J. 1990, 9 (11), 3569-66. *
CHEMICAL ABSTRACTS, Volume 114, No. 13, issued April 1991, (Columbus, Ohio, USA), P.H. KIEM et al., "Concurrent Activation of c-Myc and Inactivation of Bcl-2 by Chromosonal Translocation in a Lymphoblastic Lymphoma Cell Line"; & ONCOGENE 1990, 5 (12), 1815-19. *
NATURE, Vol. 335, (6189), 29 September 1988 (London), D.L. VAUX et al., "Bcl-2 Gene Promotors Harmopoietic Cell Survival and Cooperates with c-MYC to Immortalize Pre-B Cells", pp. 440-442. *
PROC. NATL. ACAD. SCI. (USA), Vol. 87, May 1990, J.C. REED et al., "BCL"-Mediated Tumorigenicity of a Human T-Lymphoid Cell Line: Symergy with MYC and Inhibition by BCL2 Antigene", pp 3660-3664. *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023533A1 (fr) * 1992-05-08 1993-11-25 Exemplar Corporation Test in vivo de medicaments anti-neoplasiques
WO1996014401A1 (fr) * 1994-11-03 1996-05-17 Bradley Michael John Stringer Organismes transgeniques et leurs utilisations
WO2004001367A2 (fr) * 2002-06-24 2003-12-31 MedInnova Gesellschaft für medizinische Innovationen aus akademischer Forschung mbH Systeme de test destine a la detection de maladies cancereuses
WO2004001367A3 (fr) * 2002-06-24 2004-05-06 Medinnova Ges Med Innovationen Systeme de test destine a la detection de maladies cancereuses
EP2011866A1 (fr) * 2007-07-02 2009-01-07 Ludwig Boltzmann Gesellschaft GmbH Procédé de génération d'un animal non humain avec un oncogène
WO2009003676A1 (fr) * 2007-07-02 2009-01-08 Ludwig Boltzmann Gesellschaft Gmbh Procédé de génération d'un animal non humain avec un oncogène

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