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BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint

Nature Medicine volume 19, pages 1014–1022 (2013)Cite this article

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Abstract

The B cell–specific transcription factor BACH2 is required for affinity maturation of B cells. Here we show that Bach2-mediated activation of p53 is required for stringent elimination of pre-B cells that failed to productively rearrange immunoglobulin VH-DJH gene segments. After productive VH-DJH gene rearrangement, pre-B cell receptor signaling ends BACH2-mediated negative selection through B cell lymphoma 6 (BCL6)-mediated repression of p53. In patients with pre-B acute lymphoblastic leukemia, the BACH2-mediated checkpoint control is compromised by deletions, rare somatic mutations and loss of its upstream activator, PAX5. Low levels of BACH2 expression in these patients represent a strong independent predictor of poor clinical outcome. In this study, we demonstrate that Bach2+/+ pre-B cells resist leukemic transformation by Myc through Bach2-dependent upregulation of p53 and do not initiate fatal leukemia in transplant-recipient mice. Chromatin immunoprecipitation sequencing and gene expression analyses carried out by us revealed that BACH2 competes with BCL6 for promoter binding and reverses BCL6-mediated repression of p53 and other cell cycle checkpoint–control genes. These findings identify BACH2 as a crucial mediator of negative selection at the pre-B cell receptor checkpoint and a safeguard against leukemogenesis.

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Figure 1: Bach2 and Bcl6 maintain a balance between negative selection and survival of early B cells at the pre-B cell receptor checkpoint.
Figure 2: Bach2-dependent activation of Arf and p53 is reversed by Bcl6 as a result of expression of functional μHC.
Figure 3: Bach2 mediates V(D)J recombination and μHC checkpoint control during early B cell development.
Figure 4: BACH2 mediates PAX5-dependent tumor suppression in pre-B ALL through activation of TP53.
Figure 5: BACH2 is an independent predictor of poor clinical outcome in patients with ALL.
Figure 6: Bach2 prevents leukemic transformation by Myc.

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Acknowledgements

We would like to thank H. Ye (Albert Einstein College of Medicine) for sharing Bcl6−/− mice and wild-type controls and L. Hennighausen (US National Institute of Diabetes and Digestive and Kidney Diseases) for Stat5flox/flox mice. Samples used in this research include those obtained from the Newcastle Haematology Biobank (http://www.ncl.ac.uk/nbb/collections/nhb/index.htm). We thank D.B. Kohn (University of California Los Angeles) for providing us with the retroviral envelope and packaging vectors used in this study. This work is supported by grants from the US National Institutes of Health National Cancer Institute through R01CA137060, R01CA139032, R01CA157644, R01CA172558, R01CA172558 and R01CA169458 (to M.M.), Translational Research Program grants from the Leukemia and Lymphoma Society (grants 6132-09 and 6097-10), a Leukemia and Lymphoma Society Specialized Center of Research (grant 7005-11, B.J. Druker (principal investigator)), the William Lawrence and Blanche Hughes Foundation and a Stand Up To Cancer–American Association for Cancer Research Innovative Research Grant (IRG00909 to M.M.), the California Institute for Regenerative Medicine (CIRM; TR2-01816 to M.M.) and Leukaemia and Lymphoma Research (V.R. and A.G.H.). A.M. and M.M. are Scholars of the Leukemia and Lymphoma Society. V.R. is a Leukaemia and Lymphoma Research Bennett Fellow.

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Authors and Affiliations

  1. Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA

    Srividya Swaminathan, Huimin Geng, Zhengshan Chen, Carina Ng, Christian Hurtz, Mohammed Firas Sadiyah & Markus Müschen

  2. Department of Medicine, Weill Cornell Medical College, New York, New York, USA

    Chuanxin Huang & Ari Melnick

  3. Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA

    Chuanxin Huang & Ari Melnick

  4. University of New Mexico Cancer Center, Albuquerque, New Mexico, USA

    Richard Harvey, Huining Kang & Cheryl L Willman

  5. Crump Institute for Molecular Imaging, University of California, Los Angeles, California, USA

    Björn Titz & Thomas G Graeber

  6. Cedars Sinai Medical Center, Los Angeles, California, USA

    Daniel Nowak, Gabriela B Thoennissen & H Phillip Koeffler

  7. Department of Medicine A, Hematology–Oncology, University of Muenster, Muenster, Germany

    Gabriela B Thoennissen

  8. Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK

    Vikki Rand & Andrew G Hall

  9. New York University Cancer Institute, New York University Langone Medical Center, New York, New York, USA

    William L Carroll

  10. Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan

    Kazuhiko Igarashi

  11. CREST, Japan Science and Technology Agency, Sendai, Japan

    Kazuhiko Igarashi

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  1. Srividya Swaminathan
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Contributions

S.S. and M.M. designed experiments and interpreted data. M.M. and S.S. also conceived the study and wrote the paper. S.S., C. Huang, H.G., Z.C., C.N., B.T., C. Hurtz, M.F.S., D.N., G.B.T. and V.R. performed experiments and interpreted data. H.G., R.H., H.K., V.R., H.P.K., W.L.C., C.L.W., A.G.H. and A.M. provided and characterized patient samples and clinical outcome data. T.G.G., H.P.K., K.I. and A.M. provided important reagents and mouse samples.

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Correspondence to Markus Müschen.

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Swaminathan, S., Huang, C., Geng, H. et al. BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint. Nat Med 19, 1014–1022 (2013). https://doi.org/10.1038/nm.3247

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