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Lymphoma

Early B-cell-specific inactivation of ATM synergizes with ectopic CyclinD1 expression to promote pre-germinal center B-cell lymphomas in mice

Leukemia volume 29, pages 1414–1424 (2015)Cite this article

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Abstract

Ataxia telangiectasia-mutated (ATM) kinase is a master regulator of the DNA damage response. ATM is frequently inactivated in human B-cell non-Hodgkin lymphomas, including ~50% of mantle cell lymphomas (MCLs) characterized by ectopic expression of CyclinD1. Here we report that early and robust deletion of ATM in precursor/progenitor B cells causes cell autonomous, clonal mature B-cell lymphomas of both pre- and post-germinal center (GC) origins. Unexpectedly, naive B-cell-specific deletion of ATM is not sufficient to induce lymphomas in mice, highlighting the important tumor suppressor function of ATM in immature B cells. Although EμCyclinD1 is not sufficient to induce lymphomas, EμCyclinD1 accelerates the kinetics and increases the incidence of clonal lymphomas in ATM-deficient B-cells and skews the lymphomas toward pre-GC-derived small lymphocytic neoplasms, sharing morphological features of human MCL. This is in part due to CyclinD1-driven expansion of ATM-deficient naive B cells with genomic instability, which promotes the deletions of additional tumor suppressor genes (i.e. Trp53, Mll2, Rb1 and Cdkn2a). Together these findings define a synergistic function of ATM and CyclinD1 in pre-GC B-cell proliferation and lymphomagenesis and provide a prototypic animal model to study the pathogenesis of human MCL.

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References

  1. Klein U, Dalla-Favera R . Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol 2008; 8: 22–33.

    Article  CAS  PubMed  Google Scholar 

  2. Franco S, Alt FW, Manis JP . Pathways that suppress programmed DNA breaks from progressing to chromosomal breaks and translocations. DNA Repair (Amst) 2006; 5: 1030–1041.

    Article  CAS  Google Scholar 

  3. Shiloh Y, Ziv Y . The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol 2013; 14: 197–210.

    Article  CAS  PubMed  Google Scholar 

  4. Bredemeyer AL, Sharma GG, Huang CY, Helmink BA, Walker LM, Khor KC et al. ATM stabilizes DNA double-strand-break complexes during V(D)J recombination. Nature 2006; 442: 466–470.

    Article  CAS  PubMed  Google Scholar 

  5. Pan-Hammarstrom Q, Lahdesmaki A, Zhao Y, Du L, Zhao Z, Wen S et al. Disparate roles of ATR and ATM in immunoglobulin class switch recombination and somatic hypermutation. J Exp Med 2006; 203: 99–110.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Reina-San-Martin B, Chen HT, Nussenzweig A, Nussenzweig MC . ATM is required for efficient recombination between immunoglobulin switch regions. J Exp Med 2004; 200: 1103–1110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lumsden JM, McCarty T, Petiniot LK, Shen R, Barlow C, Wynn TA et al. Immunoglobulin class switch recombination is impaired in Atm-deficient mice. J Exp Med 2004; 200: 1111–1121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lavin MF . Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol 2008; 9: 759–769.

    Article  CAS  PubMed  Google Scholar 

  9. Bea S, Valdes-Mas R, Navarro A, Salaverria I, Martin-Garcia D, Jares P et al. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc Natl Acad Sci USA 2013; 110: 18250–18255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gronbaek K, Worm J, Ralfkiaer E, Ahrenkiel V, Hokland P, Guldberg P . ATM mutations are associated with inactivation of the ARF-TP53 tumor suppressor pathway in diffuse large B-cell lymphoma. Blood 2002; 100: 1430–1437.

    Article  CAS  PubMed  Google Scholar 

  11. Wang L, Lawrence MS, Wan Y, Stojanov P, Sougnez C, Stevenson K et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med 2011; 365: 2497–2506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Stilgenbauer S, Schaffner C, Litterst A, Liebisch P, Gilad S, Bar-Shira A et al. Biallelic mutations in the ATM gene in T-prolymphocytic leukemia. Nat Med 1997; 3: 1155–1159.

    Article  CAS  PubMed  Google Scholar 

  13. Zha S, Bassing CH, Sanda T, Brush JW, Patel H, Goff PH et al. ATM-deficient thymic lymphoma is associated with aberrant tcrd rearrangement and gene amplification. J Exp Med 2010; 207: 1369–1380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bodrug SE, Warner BJ, Bath ML, Lindeman GJ, Harris AW, Adams JM . Cyclin D1 transgene impedes lymphocyte maturation and collaborates in lymphomagenesis with the myc gene. EMBO J 1994; 13: 2124–2130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lovec H, Grzeschiczek A, Kowalski MB, Moroy T . Cyclin D1/bcl-1 cooperates with myc genes in the generation of B-cell lymphoma in transgenic mice. EMBO J 1994; 13: 3487–3495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zha S, Sekiguchi J, Brush JW, Bassing CH, Alt FW . Complementary functions of ATM and H2AX in development and suppression of genomic instability. Proc Natl Acad Sci USA 2008; 105: 9302–9306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kraus M, Alimzhanov MB, Rajewsky N, Rajewsky K . Survival of resting mature B lymphocytes depends on BCR signaling via the Igalpha/beta heterodimer. Cell 2004; 117: 787–800.

    Article  CAS  PubMed  Google Scholar 

  18. Rickert RC, Rajewsky K, Roes J . Impairment of T-cell-dependent B-cell responses and B-1 cell development in CD19-deficient mice. Nature 1995; 376: 352–355.

    Article  CAS  PubMed  Google Scholar 

  19. Hobeika E, Thiemann S, Storch B, Jumaa H, Nielsen PJ, Pelanda R et al. Testing gene function early in the B cell lineage in mb1-cre mice. Proc Natl Acad Sci USA 2006; 103: 13789–13794.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yamamoto K, Wang Y, Jiang W, Liu X, Dubois RL, Lin CS et al. Kinase-dead ATM protein causes genomic instability and early embryonic lethality in mice. J Cell Biol 2012; 198: 305–313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Klein U, Lia M, Crespo M, Siegel R, Shen Q, Mo T et al. The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer Cell 2010; 17: 28–40.

    Article  CAS  PubMed  Google Scholar 

  22. Gostissa M, Yan CT, Bianco JM, Cogne M, Pinaud E, Alt FW . Long-range oncogenic activation of Igh-c-myc translocations by the Igh 3' regulatory region. Nature 2009; 462: 803–807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zha S, Sekiguchi J, Brush JW, Bassing CH, Alt FW . Complementary functions of ATM and H2AX in development and suppression of genomic instability. Proc Natl Acad Sci USA 2008; 105: 9302–9306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Franco S, Gostissa M, Zha S, Lombard DB, Murphy MM, Zarrin AA et al. H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. Mol Cell 2006; 21: 201–214.

    Article  CAS  PubMed  Google Scholar 

  25. Jares P, Colomer D, Campo E . Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics. Nat Rev Cancer 2007; 7: 750–762.

    Article  CAS  PubMed  Google Scholar 

  26. Kwon K, Hutter C, Sun Q, Bilic I, Cobaleda C, Malin S et al. Instructive role of the transcription factor E2A in early B lymphopoiesis and germinal center B cell development. Immunity 2008; 28: 751–762.

    Article  CAS  PubMed  Google Scholar 

  27. Ziv Y, Bielopolski D, Galanty Y, Lukas C, Taya Y, Schultz DC et al. Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM and KAP-1 dependent pathway. Nat Cell Biol 2006; 8: 870–U142.

    Article  CAS  PubMed  Google Scholar 

  28. Borghesani PR, Alt FW, Bottaro A, Davidson L, Aksoy S, Rathbun GA et al. Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice. Proc Natl Acad Sci USA 2000; 97: 3336–3341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pelanda R, Braun U, Hobeika E, Nussenzweig MC, Reth M . B cell progenitors are arrested in maturation but have intact VDJ recombination in the absence of Ig-alpha and Ig-beta. J Immunol 2002; 169: 865–872.

    Article  CAS  PubMed  Google Scholar 

  30. Minegishi Y, Coustan-Smith E, Rapalus L, Ersoy F, Campana D, Conley ME . Mutations in Igalpha (CD79a) result in a complete block in B-cell development. J Clin Invest 1999; 104: 1115–1121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Walsh SH, Thorselius M, Johnson A, Soderberg O, Jerkeman M, Bjorck E et al. Mutated VH genes and preferential VH3-21 use define new subsets of mantle cell lymphoma. Blood 2003; 101: 4047–4054.

    Article  CAS  PubMed  Google Scholar 

  32. Lumsden JM, McCarty T, Petiniot LK, Shen R, Barlow C, Wynn TA et al. Immunoglobulin class switch recombination is impaired in Atm-deficient mice. J Exp Med 2004; 200: 1111–1121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Reina-San-Martin B, Chen HT, Nussenzweig A, Nussenzweig MC . ATM is required for efficient recombination between immunoglobulin switch regions. J Exp Med 2004; 200: 1103–1110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Callen E, Jankovic M, Difilippantonio S, Daniel JA, Chen HT, Celeste A et al. ATM prevents the persistence and propagation of chromosome breaks in lymphocytes. Cell 2007; 130: 63–75.

    Article  CAS  PubMed  Google Scholar 

  35. Kikushige Y, Ishikawa F, Miyamoto T, Shima T, Urata S, Yoshimoto G et al. Self-renewing hematopoietic stem cell is the primary target in pathogenesis of human chronic lymphocytic leukemia. Cancer Cell 2011; 20: 246–259.

    Article  CAS  PubMed  Google Scholar 

  36. Vaites LP, Lian Z, Lee EK, Yin B, DeMicco A, Bassing CH et al. ATM deficiency augments constitutively nuclear cyclin D1-driven genomic instability and lymphomagenesis. Oncogene 2014; 33: 129–133.

    Article  CAS  PubMed  Google Scholar 

  37. Vaites LP, Lee EK, Lian Z, Barbash O, Roy D, Wasik M et al. The Fbx4 tumor suppressor regulates Cyclin D1 accumulation and prevents neoplastic transformation. Mol Cell Biol 2011; 31: 4513–4523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Santra MK, Wajapeyee N, Green MR . F-box protein FBXO31 mediates cyclin D1 degradation to induce G1 arrest after DNA damage. Nature 2009; 459: 722–725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Vaites LP, Lian Z, Lee EK, Yin B, Demicco A, Bassing CH et al. ATM deficiency augments constitutively nuclear cyclin D1-driven genomic instability and lymphomagenesis. Oncogene 2013; 33: 129–133.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Gladden AB, Woolery R, Aggarwal P, Wasik MA, Diehl JA . Expression of constitutively nuclear cyclin D1 in murine lymphocytes induces B-cell lymphoma. Oncogene 2006; 25: 998–1007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ciemerych MA, Sicinski P . Cell cycle in mouse development. Oncogene 2005; 24: 2877–2898.

    Article  CAS  PubMed  Google Scholar 

  42. Carthon BC, Neumann CA, Das M, Pawlyk B, Li T, Geng Y et al. Genetic replacement of cyclin D1 function in mouse development by cyclin D2. Mol Cell Biol 2005; 25: 1081–1088.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Peled JU, Yu JJ, Venkatesh J, Bi E, Ding BB, Krupski-Downs M et al. Requirement for cyclin D3 in germinal center formation and function. Cell Res 2010; 20: 631–646.

    Article  CAS  PubMed  Google Scholar 

  44. Cato MH, Chintalapati SK, Yau IW, Omori SA, Rickert RC . Cyclin D3 is selectively required for proliferative expansion of germinal center B cells. Mol Cell Biol 2011; 31: 127–137.

    Article  CAS  PubMed  Google Scholar 

  45. Cattoretti G, Pasqualucci L, Ballon G, Tam W, Nandula SV, Shen Q et al. Deregulated BCL6 expression recapitulates the pathogenesis of human diffuse large B cell lymphomas in mice. Cancer Cell 2005; 7: 445–455.

    Article  CAS  PubMed  Google Scholar 

  46. Zullo K, Amengual JE, O'Connor OA, Scotto L . Murine models in mantle cell lymphoma. Best Pract Res Clin Haematol 2012; 25: 153–163.

    Article  PubMed  Google Scholar 

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Acknowledgements

We wish to thank Dr Frederick W Alt for providing the ATM conditional mouse model, Dr Klaus Rajewsky for providing the CD19Cre and CD21Cre mice and Dr Michael Reth for providing the Mb1Cre mice. We also wish to thank Ms Hongyan Tang and Mr Denis Loredan for their technical assistance. We thank Jennifer L Crowe for critical reading of the manuscript. Research reported in this publication was supported by the NIH/NCI 1RO1CA158073, American Cancer Society (124300-RSG-13-038 DMC) for SZ and NIH/NCI PO1 CA174653 for SZ and GB. SZ was a St Baldrick’s Scholar for Pediatric Cancer and is a Leukemia Lymphomas Society Scholar.

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Authors and Affiliations

  1. Institute for Cancer Genetics, College for Physicians and Surgeons, Columbia University, New York, NY, USA

    K Yamamoto, B J Lee, C Li, R L Dubois & S Zha

  2. Graduate Program for Pathobiology and Molecular Medicine, College for Physicians and Surgeons, Columbia University, New York, NY, USA

    K Yamamoto

  3. Centre for Biological Signaling Studies BIOSS, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany,

    E Hobeika

  4. Department of Molecular Immunology, Albert-Ludwigs-Universität Freiburg and Max Planck Institute for Immunobiology, Freiburg, Germany,

    E Hobeika

  5. Department of Pathology and Cell Biology, College for Physicians and Surgeons, Columbia University, New York, NY, USA,

    G Bhagat & S Zha

  6. Department of Pediatrics, College for Physicians and Surgeons, Columbia University, New York, NY, USA,

    S Zha

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Correspondence to S Zha.

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Yamamoto, K., Lee, B., Li, C. et al. Early B-cell-specific inactivation of ATM synergizes with ectopic CyclinD1 expression to promote pre-germinal center B-cell lymphomas in mice. Leukemia 29, 1414–1424 (2015). https://doi.org/10.1038/leu.2015.41

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