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

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.
AuthorsSrividya 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 Melnick, Markus Müschen
JournalNature medicine (Nat Med) Vol. 19 Issue 8 Pg. 1014-22 (Aug 2013) ISSN: 1546-170X [Electronic] United States
PMID23852341 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • BACH2 protein, human
  • BCL6 protein, human
  • Bach2 protein, mouse
  • Basic-Leucine Zipper Transcription Factors
  • DNA-Binding Proteins
  • Immunoglobulin mu-Chains
  • PAX5 Transcription Factor
  • PAX5 protein, human
  • Pre-B Cell Receptors
  • Proto-Oncogene Proteins c-bcl-6
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • STAT5 Transcription Factor
  • Tumor Suppressor Protein p53
  • Green Fluorescent Proteins
Topics
  • Animals
  • Basic-Leucine Zipper Transcription Factors (genetics, metabolism)
  • Cell Death
  • Cell Differentiation (genetics)
  • Cell Survival (genetics)
  • Cell Transformation, Neoplastic (pathology)
  • DNA-Binding Proteins (metabolism)
  • Gene Deletion
  • Gene Expression Regulation, Leukemic
  • Green Fluorescent Proteins (metabolism)
  • Immunoglobulin mu-Chains (metabolism)
  • Mice
  • Molecular Sequence Data
  • PAX5 Transcription Factor (metabolism)
  • Pre-B Cell Receptors (metabolism)
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma (genetics, pathology)
  • Precursor Cells, B-Lymphoid (metabolism, pathology)
  • Proto-Oncogene Proteins c-bcl-6
  • Proto-Oncogene Proteins c-myc (metabolism)
  • RNA, Messenger (genetics, metabolism)
  • STAT5 Transcription Factor (metabolism)
  • Treatment Outcome
  • Tumor Suppressor Protein p53 (metabolism)
  • V(D)J Recombination (genetics)

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