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BCR-ABL Studies

Increase in mutant frequencies in mice expressing the BCR-ABL activated tyrosine kinase

Abstract

The acquisition of the Philadelphia (Ph) chromosome (or BCR-ABL translocation) represents a detrimental pathophysiological event in humans. The activated tyrosine kinases, which are produced by this translocation, are associated with fatal hematological malignancies. The initial molecular dissection of BCR-ABL has linked the expression of this constitutively activated kinase with enhanced genomic instability. We directly evaluated the consequence of BCR-ABL expression on genomic instability using the Big Blue in vivo mutagenesis mouse system. We report that the expression of BCR-ABL in both spleens and kidneys confers a mutator phenotype represented by a statistically significant elevation in mutant frequencies.

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References

  1. Heisterkamp N, Jenester G, ten Hoeve J, Zovich D, Pattengale PK, Grofen J . Acute leukemia in bcr/abl transgenic mice Nature 1990 344: 251–253

    CAS  Google Scholar 

  2. Honda H, Oda H, Suzuki T, Takahashi T, Witte ON, Ozawa K, Ishikawa T, Yazaki Y, Hirai H . Development of acute lymphoblastic leukemia and myeloproliferative disorder in transgenic mice expressing p210bcr/abl: a novel transgenic model for human Ph1-positive leukemias Blood 1998 91: 2067–2075

    CAS  Google Scholar 

  3. Voncken JW, Kaartinen V, Pattengale PK, Germeraad WT, Groffen J, Heisterkamp N . BCR/ABL P210 and P190 cause distinct leukemia in transgenic mice Blood 1995 86: 4603- 4611

    Google Scholar 

  4. Daley GQ, Van Etten RA, Baltimore D . Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome Science 1990 247: 824–830

    CAS  Google Scholar 

  5. Tauchi T, Boswell HS, Leibowitz D, Broxmeyer HE . Coupling between p210bcr-abl and Shc and Grb2 adaptor proteins in hematopoietic cells permits growth factor receptor-independent link to ras activation pathway J Exp Med 1994 179: 167–175

    CAS  Google Scholar 

  6. Salgia R, Brunkhorst B, Pisick E, Li JL, Lo SH, Chen L, Griffin JD . Increased tyrosine phosphorylation of focal adhesion proteins in myeloid cell lines expressing p210BCR/ABL Oncogene 1995 11: 1149–1155

    CAS  Google Scholar 

  7. Cortez D, Stoica G, Pierce JH, Pendergast AM . The BCR-ABL tyrosine kinase inhibits apoptosis by activating a Ras-dependent signaling pathway Oncogene 1996 13: 2589–2594

    CAS  Google Scholar 

  8. Bernstein R . Cytogenetics of chronic myelogenous leukemia Semin Hematol 1998 25: 20–34

    Google Scholar 

  9. Voncken JW, Morris C, Pattengale P, Dennert G, Kikly C, Groffen J, Heisterkamp N . Clonal development and karyotype evolution during leukemogenesis of BCR/ABL transgenic mice Blood 1992 79: 1029–1036

    CAS  Google Scholar 

  10. Laneuville P, Sun G, Timm M, Vekemans M . Clonal evolution in a myeloid cell line transformed to interleukin-3 independent growth by retroviral transduction and expression of p210bcr/abl Blood 1992 80: 1788–1797

    CAS  Google Scholar 

  11. Bedi A, Zehnbauer BA, Barber JP, Sharkis SJ, Jones RJ . Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia Blood 1994 83: 2038–2044

    CAS  Google Scholar 

  12. Laneuville P, Heisterkamp N, Groffen J . Expression of the chronic myelogenous leukemia- associated p210bcr/abl oncoprotein in a murine IL-3 dependent myeloid cell line Oncogene 1991 6: 275–282

    CAS  Google Scholar 

  13. Provost GS, Kretz PL, Hamner RT, Matthews CD, Rogers B, Lundberg KS, Dycaico MJ, Short JM . Transgenic systems for in vivo mutation analysis Mutat Res 1993 288: 133–149

    CAS  Google Scholar 

  14. Piegorsch WW, Bailer AJ . Statistical approaches for analyzing mutational spectra: some recommendations for categorical data Genetics 1994 136: 403–416

    CAS  Google Scholar 

  15. Voncken JW, Griffiths S, Greaves MF, Pattengale PK, Heisterkamp N, Groffen J . Restricted oncogenicity of BCR/ABL p190 in transgenic mice Cancer Res 1992 52: 4534–4539

    CAS  Google Scholar 

  16. Loeb LA . Microsatellite instability: marker of a mutator phenotype in cancer Cancer Res 1994 54: 5059–5063

    CAS  Google Scholar 

  17. Loeb LA, Christians FC . Multiple mutations in human cancers Mutat Res 1996 350: 279- 286

    Google Scholar 

  18. Melo JV . The molecular biology of chronic myeloid leukemia Leukemia 1996 10: 751–756

    CAS  Google Scholar 

  19. Laneuville P . Abl tyrosine protein kinase Semin Immunol 1995 7: 255–266

    CAS  Google Scholar 

  20. Canitrot Y, Lautier D, Laurent G, Frechet M, Ahmed A, Turhan AG, Salles B, Cazaux C, Hoffmann J . Mutator phenotype of BCR-ABL transfected Ba/F3 cell lines and its association with enhanced expression of DNA polymerase β Oncogene 1999 18: 2676–2680

    CAS  Google Scholar 

  21. van der Kuip H, Carius B, Huber C, Fischer T . Lack of DNA replication and repair factor RFC- P140 protein expression in CML Blood 1998 92: 4872 (Abstr.)

    Google Scholar 

  22. Cariello NF, Gorelick NJ . Database and software for the analysis of mutations at the LacI gene in both transgenic rodents and bacteria Environ Mol Mutagen 1996 28: 397–404

    CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank Drs N Heisterkamp and J Groffen for supplying us with the P190BCR-ABL mice. This work would not have been possible without the help of colleagues in the molecular oncology group especially in Drs Allan Peaterson and Pierre Laneuville's laboratories. HFS is the recipient of a Cedar Cancer Institute and the Royal Victoria Hospital Kaufmann studentships. This work was supported by grant No. MT13253 from the Medical Research Council (MRC) of Canada to PL.

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Salloukh, H., Laneuville, P. Increase in mutant frequencies in mice expressing the BCR-ABL activated tyrosine kinase. Leukemia 14, 1401–1404 (2000). https://doi.org/10.1038/sj.leu.2401855

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