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

Lookup NU author(s): Dr Vikki Rand, Dr Andrew Hall


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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.

Publication metadata

Author(s): Swaminathan S, Huang C, Geng H, Chen Z, Harvey R, Kang H, Ng C, Titz B, Hurtz C, Sadiyah MF, Nowak D, Thoennissen GB, Rand V, Graeber TG, Koeffler HP, Carroll WL, Willman CL, Hall AG, Igarashi K, Melnick A, Müschen M

Publication type: Article

Publication status: Published

Journal: Nature Medicine

Year: 2013

Volume: 19

Issue: 8

Pages: 1014-1022

Print publication date: 14/07/2013

ISSN (print): 1078-8956

ISSN (electronic): 1546-170X

Publisher: Nature Publishing Group


DOI: 10.1038/nm.3247


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Funder referenceFunder name
Leukaemia and Lymphoma Research
Scholars of the Leukemia and Lymphoma Society
William Lawrence and Blanche Hughes Foundation
6097-10Leukemia and Lymphoma Society
6132-09Leukemia and Lymphoma Society
7005-11Leukemia and Lymphoma Society Specialized Center of Research
IRG00909Stand Up To Cancer-American Association for Cancer Research Innovative Research
R01CA137060US National Institutes of Health National Cancer Institute
R01CA172558US National Institutes of Health National Cancer Institute
R01CA139032US National Institutes of Health National Cancer Institute
R01CA157644US National Institutes of Health National Cancer Institute
R01CA169458US National Institutes of Health National Cancer Institute
TR2-01816California Institute for Regenerative Medicine (CIRM)