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BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint.
- Source :
-
Nature medicine [Nat Med] 2013 Aug; Vol. 19 (8), pp. 1014-22. Date of Electronic Publication: 2013 Jul 14. - Publication Year :
- 2013
-
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.
- Subjects :
- Animals
Basic-Leucine Zipper Transcription Factors genetics
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
Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology
Precursor Cells, B-Lymphoid metabolism
Precursor Cells, B-Lymphoid pathology
Proto-Oncogene Proteins c-bcl-6
Proto-Oncogene Proteins c-myc metabolism
RNA, Messenger genetics
RNA, Messenger metabolism
STAT5 Transcription Factor metabolism
Treatment Outcome
V(D)J Recombination genetics
Basic-Leucine Zipper Transcription Factors metabolism
Pre-B Cell Receptors metabolism
Tumor Suppressor Protein p53 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1546-170X
- Volume :
- 19
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Nature medicine
- Publication Type :
- Academic Journal
- Accession number :
- 23852341
- Full Text :
- https://doi.org/10.1038/nm.3247