TitleBACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint.
Publication TypeJournal Article
Year of Publication2013
AuthorsSwaminathan, Srividya, Huang ChuanXin, Geng Huimin, Chen Zhengshan, Harvey Richard, Kang Huining, Ng Carina, Titz Björn, Hurtz Christian, Sadiyah Mohammed Firas, Nowak Daniel, Thoennissen Gabriela B., Rand Vikki, Graeber Thomas G., H Koeffler Phillip, Carroll William L., Willman Cheryl L., Hall Andrew G., Igarashi Kazuhiko, Melnick Ari, and Müschen Markus
JournalNat Med
Volume19
Issue8
Pagination1014-22
Date Published2013 Aug
ISSN1546-170X
KeywordsAnimals, Basic-Leucine Zipper Transcription Factors, Cell Death, Cell Differentiation, Cell Survival, Cell Transformation, Neoplastic, DNA-Binding Proteins, Gene Deletion, Gene Expression Regulation, Leukemic, Green Fluorescent Proteins, Immunoglobulin mu-Chains, Mice, Molecular Sequence Data, PAX5 Transcription Factor, Pre-B Cell Receptors, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Precursor Cells, B-Lymphoid, Proto-Oncogene Proteins c-bcl-6, Proto-Oncogene Proteins c-myc, RNA, Messenger, STAT5 Transcription Factor, Treatment Outcome, Tumor Suppressor Protein p53, V(D)J Recombination
Abstract

<p>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.</p>

DOI10.1038/nm.3247
Alternate JournalNat Med
PubMed ID23852341
PubMed Central IDPMC3954721
Grant ListR01 CA157644 / CA / NCI NIH HHS / United States
R01 CA172558 / CA / NCI NIH HHS / United States
U01 CA157937 / CA / NCI NIH HHS / United States
R01CA169458 / CA / NCI NIH HHS / United States
R01CA172558 / CA / NCI NIH HHS / United States
R01CA139032 / CA / NCI NIH HHS / United States
R01 CA137060 / CA / NCI NIH HHS / United States
R01CA137060 / CA / NCI NIH HHS / United States
R01 CA169458 / CA / NCI NIH HHS / United States
R01 CA139032 / CA / NCI NIH HHS / United States
R01CA157644 / CA / NCI NIH HHS / United States