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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Authors | 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 Melnick, Markus Müschen |
Journal | Nature medicine
(Nat Med)
Vol. 19
Issue 8
Pg. 1014-22
(Aug 2013)
ISSN: 1546-170X [Electronic] United States |
PMID | 23852341
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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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
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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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