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

Nat Med. 2013 Aug;19(8):1014-22. doi: 10.1038/nm.3247. Epub 2013 Jul 14.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / 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
  • 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
  • Tumor Suppressor Protein p53 / metabolism*
  • V(D)J Recombination / genetics

Substances

  • 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

Associated data

  • GENBANK/HE578163
  • GENBANK/HE578164
  • GENBANK/HE578165
  • GENBANK/HE578166
  • GENBANK/HE578168
  • GENBANK/HE578169
  • GENBANK/HE578170
  • GENBANK/HE578173
  • GENBANK/HE578176
  • GEO/GSE20987
  • GEO/GSE24814
  • GEO/GSE28460
  • GEO/GSE30883
  • GEO/GSE30889
  • GEO/GSE30928
  • GEO/GSE31027
  • GEO/GSE34941
  • GEO/GSE41042
  • GEO/GSE44420