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

Srividya Swaminathan, Chuanxin Huang, Huimin Geng, Zhengshan Chen, Richard Harvey, Huining Kang, Carina Ng, Björn Titz, Christian Hurtz, Mohammed Firas Sadiyah, Daniel Nowak, Gabriela B. Thoennissen, Vikki Rand, Thomas G. Graeber, H. Phillip Koeffler, William L. Carroll, Cheryl L. Willman, Andrew G. Hall, Kazuhiko Igarashi, Ari MelnickMarkus Müschen

Research output: Contribution to journalArticlepeer-review

69 Citations (Scopus)

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 V H-DJ H gene segments. After productive V H-DJ H 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.

Original languageEnglish
Pages (from-to)1014-1022
Number of pages9
JournalNature Medicine
Volume19
Issue number8
DOIs
Publication statusPublished - 2013 Aug

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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