title: 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.
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA.
authors.forename: Srividya
authors.initials: S
authors.lastname: Swaminathan
authors.forename: Chuanxin
authors.initials: C
authors.lastname: Huang
authors.forename: Huimin
authors.initials: H
authors.lastname: Geng
authors.forename: Zhengshan
authors.initials: Z
authors.lastname: Chen
authors.forename: Richard
authors.initials: R
authors.lastname: Harvey
authors.forename: Huining
authors.initials: H
authors.lastname: Kang
authors.forename: Carina
authors.initials: C
authors.lastname: Ng
authors.forename: Björn
authors.initials: B
authors.lastname: Titz
authors.forename: Christian
authors.initials: C
authors.lastname: Hurtz
authors.forename: Mohammed Firas
authors.initials: MF
authors.lastname: Sadiyah
authors.forename: Daniel
authors.initials: D
authors.lastname: Nowak
authors.forename: Gabriela B
authors.initials: GB
authors.lastname: Thoennissen
authors.forename: Vikki
authors.initials: V
authors.lastname: Rand
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Graeber
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Hall
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Igarashi
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D002454:Cell Differentiation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D017353:Gene Deletion; D015973:Gene Expression Regulation, Leukemic; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007148:Immunoglobulin mu-Chains / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D051757:PAX5 Transcription Factor / Q000378:metabolism; D054420:Pre-B Cell Receptors / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism / Q000473:pathology; D051560:Proto-Oncogene Proteins c-bcl-6; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D060152:V(D)J Recombination / Q000235:genetics
chemical_list: C491123:BACH2 protein, human; C084103:BCL6 protein, human; C102109:Bach2 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D007148:Immunoglobulin mu-Chains; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D054420:Pre-B Cell Receptors; D051560:Proto-Oncogene Proteins c-bcl-6; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; D016159:Tumor Suppressor Protein p53; D049452:Green Fluorescent Proteins