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Chronic Myeloproliferative Neoplasias

BCR/ABL induces chromosomal instability after genotoxic stress and alters the cell death threshold

Leukemia volume 23, pages 279–286 (2009)Cite this article

Abstract

Earlier reports have suggested that the BCR/ABL oncogene, associated with chronic myeloid leukemia, induces a mutator phenotype; however, it is unclear whether this leads to long-term changes in chromosomes and whether the phenotype is found in primary chronic myelogeneous leukemia (CML) cells. We have addressed both these issues. BCR/ABL-expressing cell lines show an increase in DNA breaks after treatment with etoposide as compared to control cells. However, although BCR/ABL-expressing cell lines have an equivalent cell survival, they have an increase in chromosomal translocations after DNA repair as compared to control cells. This demonstrates that BCR/ABL expression decreases the fidelity of DNA repair. To see whether this is true in primary CML samples, normal CD34+ progenitor cells and CML progenitor cells were treated with etoposide. CML progenitor cells have equivalent survival but have an increase in DNA double-strand breaks (DSBs). Spectral karyotyping demonstrates new chromosomal translocations in CML cells, but not normal progenitor cells, consistent with error-prone DNA repair. Taken together, these data demonstrate that BCR/ABL enhances the accumulation of DSBs and alters the apoptotic threshold in CML leading to error-prone DNA repair.

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References

  1. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344: 1031–1037.

    CAS  PubMed  Google Scholar 

  2. Pear WS, Miller JP, Xu L, Pui JC, Soffer B, Quackenbush RC et al. Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving P210 bcr/abl-transduced bone marrow. Blood 1998; 92: 3780–3792.

    CAS  PubMed  Google Scholar 

  3. Wong S, Witte ON . The BCR-ABL story: bench to bedside and back. Annu Rev Immunol 2004; 22: 247–306.

    Article  CAS  PubMed  Google Scholar 

  4. Giehl M, Fabarius A, Frank O, Hochhaus A, Hafner M, Hehlmann R et al. Centrosome aberrations in chronic myeloid leukemia correlate with stage of disease and chromosomal instability. Leukemia 2005; 19: 1192–1197.

    Article  CAS  PubMed  Google Scholar 

  5. Gribble SM, Sinclair PB, Grace C, Green AR, Nacheva EP . Comparative analysis of G-banding, chromosome painting, locus-specific fluorescence in situ hybridization, and comparative genomic hybridization in chronic myeloid leukemia blast crisis. Cancer Genet Cytogenet 1999; 111: 7–17.

    Article  CAS  PubMed  Google Scholar 

  6. Johansson B, Fioretos T, Mitelman F . Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol 2002; 107: 76–94.

    Article  CAS  PubMed  Google Scholar 

  7. Fialkow PJ, Jacobson RJ, Papayannopoulou T . Chronic myelocytic leukemia: clonal origin in a stem cell common to the granulocyte, erythrocyte, platelet and monocyte/macrophage. Am J Med 1977; 63: 125–130.

    CAS  PubMed  Google Scholar 

  8. Gaymes TJ, Mufti GJ, Rassool FV . Myeloid leukemias have increased activity of the nonhomologous end-joining pathway and concomitant DNA misrepair that is dependent on the Ku70/86 heterodimer. Cancer Res 2002; 62: 2791–2797.

    CAS  PubMed  Google Scholar 

  9. Amos TA, Lewis JL, Grand FH, Gooding RP, Goldman JM, Gordon MY . Apoptosis in chronic myeloid leukaemia: normal responses by progenitor cells to growth factor deprivation, X-irradiation and glucocorticoids. Br J Haematol 1995; 91: 387–393.

    Article  CAS  PubMed  Google Scholar 

  10. Bedi A, Barber JP, Bedi GC, el-Deiry WS, Sidransky D, Vala MS et al. BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage: a mechanism of resistance to multiple anticancer agents. Blood 1995; 86: 1148–1158.

    CAS  PubMed  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  PubMed  Google Scholar 

  12. 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  PubMed  Google Scholar 

  13. Nowicki MO, Falinski R, Koptyra M, Slupianek A, Stoklosa T, Gloc E et al. BCR/ABL oncogenic kinase promotes unfaithful repair of the reactive oxygen species-dependent DNA double-strand breaks. Blood 2004; 104: 3746–3753.

    Article  CAS  PubMed  Google Scholar 

  14. Slupianek A, Schmutte C, Tombline G, Nieborowska-Skorska M, Hoser G, Nowicki MO et al. BCR/ABL regulates mammalian RecA homologs, resulting in drug resistance. Mol Cell 2001; 8: 795–806.

    Article  CAS  PubMed  Google Scholar 

  15. Koptyra M, Falinski R, Nowicki MO, Stoklosa T, Majsterek I, Nieborowska-Skorska M et al. BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance. Blood 2006; 108: 319–327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sattler M, Verma S, Shrikhande G, Byrne CH, Pride YB, Winkler T et al. The BCR/ABL tyrosine kinase induces production of reactive oxygen species in hematopoietic cells. J Biol Chem 2000; 275: 24273–24278.

    Article  CAS  PubMed  Google Scholar 

  17. Dierov J, Dierova R, Carroll M . BCR/ABL translocates to the nucleus and disrupts an ATR-dependent intra-S phase checkpoint. Cancer Cell 2004; 5: 275–285.

    Article  CAS  PubMed  Google Scholar 

  18. Deutsch E, Dugray A, AbdulKarim B, Marangoni E, Maggiorella L, Vaganay S et al. BCR-ABL down-regulates the DNA repair protein DNA-PKcs. Blood 2001; 97: 2084–2090.

    Article  CAS  PubMed  Google Scholar 

  19. Deutsch E, Jarrousse S, Buet D, Dugray A, Bonnet ML, Vozenin-Brotons MC et al. Down-regulation of BRCA1 in BCR-ABL-expressing hematopoietic cells. Blood 2003; 101: 4583–4588.

    Article  CAS  PubMed  Google Scholar 

  20. Klucher KM, Lopez DV, Daley GQ . Secondary mutation maintains the transformed state in BaF3 cells with inducible BCR/ABL expression. Blood 1998; 91: 3927–3934.

    CAS  PubMed  Google Scholar 

  21. Singh NP, McCoy MT, Tice RR, Schneider EL . A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 1988; 175: 184–191.

    Article  CAS  PubMed  Google Scholar 

  22. Liyanage M, Coleman A, du Manoir S, Veldman T, McCormack S, Dickson RB et al. Multicolour spectral karyotyping of mouse chromosomes. Nat Genet 1996; 14: 312–315.

    Article  CAS  PubMed  Google Scholar 

  23. Padilla-Nash HM, Heselmeyer-Haddad K, Wangsa D, Zhang H, Ghadimi BM, Macville M et al. Jumping translocations are common in solid tumor cell lines and result in recurrent fusions of whole chromosome arms. Genes Chromosomes Cancer 2001; 30: 349–363.

    Article  CAS  PubMed  Google Scholar 

  24. McCullogh C, Searle S . Generalized, linear, and mixed models. John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2001.

  25. Koptyra M, Cramer K, Slupianek A, Richardson C, Skorski T . BCR/ABL promotes accumulation of chromosomal aberrations induced by oxidative and genotoxic stress. Leukemia 2008; 22: 1969–1972.

    Article  CAS  PubMed  Google Scholar 

  26. Nieborowska-Skorska M, Stoklosa T, Datta M, Czechowska A, Rink L, Slupianek A et al. ATR-Chk1 axis protects BCR/ABL leukemia cells from the lethal effect of DNA double-strand breaks. Cell Cycle 2006; 5: 994–1000.

    Article  CAS  PubMed  Google Scholar 

  27. Giehl M, Fabarius A, Frank O, Erben P, Zheng C, Hafner M et al. Expression of the p210BCR-ABL oncoprotein drives centrosomal hypertrophy and clonal evolution in human U937 cells. Leukemia 2007; 21: 1971–1976.

    Article  CAS  PubMed  Google Scholar 

  28. Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355: 2408–2417.

    Article  CAS  PubMed  Google Scholar 

  29. Deininger MW, Cortes J, Paquette R, Park B, Hochhaus A, Baccarani M et al. The prognosis for patients with chronic myeloid leukemia who have clonal cytogenetic abnormalities in Philadelphia chromosome-negative cells. Cancer 2007; 110: 1509–1519.

    Article  PubMed  Google Scholar 

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Acknowledgements

MC is a Clinical Scholar of the Leukemia Lymphoma Society and is supported by NCI R01CA100885. This research was supported (in part) by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. We thank Tomasz Skorski and colleagues for sharing data prior to publication. JD, PVS, BAB and HP-N performed experiments. MEP performed statistical analysis. TR provided reagents and expertise. MC supervised the experiments and wrote the papers.

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Author notes

  1. J Dierov and P V Sanchez: These two authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    J Dierov, P V Sanchez, B A Burke & M Carroll

  2. Section of Cancer Genomics, Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    H Padilla-Nash & T Ried

  3. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA

    M E Putt

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  1. J Dierov
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  2. P V Sanchez
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  7. M Carroll
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Correspondence to M Carroll.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Dierov, J., Sanchez, P., Burke, B. et al. BCR/ABL induces chromosomal instability after genotoxic stress and alters the cell death threshold. Leukemia 23, 279–286 (2009). https://doi.org/10.1038/leu.2008.308

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