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

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BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint. / Swaminathan, Srividya; Huang, Chuanxin; Geng, Huimin; Chen, Zhengshan; Harvey, Richard; Kang, Huining; Ng, Carina; Titz, Björn; Hurtz, Christian; Sadiyah, Mohammed Firas; Nowak, Daniel; Thoennissen, Gabriela B; Rand, Vikki; Graeber, Thomas G; Koeffler, H Phillip; Carroll, William L; Willman, Cheryl L; Hall, Andrew G; Igarashi, Kazuhiko; Melnick, Ari; Müschen, Markus.

In: NAT MED, Vol. 19, No. 8, 08.2013, p. 1014-22.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Swaminathan, S, Huang, C, Geng, H, Chen, Z, Harvey, R, Kang, H, Ng, C, Titz, B, Hurtz, C, Sadiyah, MF, Nowak, D, Thoennissen, GB, Rand, V, Graeber, TG, Koeffler, HP, Carroll, WL, Willman, CL, Hall, AG, Igarashi, K, Melnick, A & Müschen, M 2013, 'BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint', NAT MED, vol. 19, no. 8, pp. 1014-22. https://doi.org/10.1038/nm.3247

APA

Swaminathan, S., Huang, C., Geng, H., Chen, Z., Harvey, R., Kang, H., Ng, C., Titz, B., Hurtz, C., Sadiyah, M. F., Nowak, D., Thoennissen, G. B., Rand, V., Graeber, T. G., Koeffler, H. P., Carroll, W. L., Willman, C. L., Hall, A. G., Igarashi, K., ... Müschen, M. (2013). BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint. NAT MED, 19(8), 1014-22. https://doi.org/10.1038/nm.3247

Vancouver

Swaminathan S, Huang C, Geng H, Chen Z, Harvey R, Kang H et al. BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint. NAT MED. 2013 Aug;19(8):1014-22. https://doi.org/10.1038/nm.3247

Bibtex

@article{cec9770d6db54920b1a6c8103c0e9484,
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.",
keywords = "Animals, B-Cell-Specific Activator Protein, Basic-Leucine Zipper Transcription Factors, Cell Death, Cell Differentiation, Cell Survival, Cell Transformation, Neoplastic, DNA-Binding Proteins, Gene Deletion, Gene Expression Regulation, Leukemic, Green Fluorescent Proteins, Immunoglobulin mu-Chains, Mice, Molecular Sequence Data, Pre-B Cell Receptors, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Precursor Cells, B-Lymphoid, Proto-Oncogene Proteins c-myc, RNA, Messenger, STAT5 Transcription Factor, Treatment Outcome, Tumor Suppressor Protein p53, V(D)J Recombination",
author = "Srividya Swaminathan and Chuanxin Huang and Huimin Geng and Zhengshan Chen and Richard Harvey and Huining Kang and Carina Ng and Bj{\"o}rn Titz and Christian Hurtz and Sadiyah, {Mohammed Firas} and Daniel Nowak and Thoennissen, {Gabriela B} and Vikki Rand and Graeber, {Thomas G} and Koeffler, {H Phillip} and Carroll, {William L} and Willman, {Cheryl L} and Hall, {Andrew G} and Kazuhiko Igarashi and Ari Melnick and Markus M{\"u}schen",
year = "2013",
month = aug,
doi = "10.1038/nm.3247",
language = "English",
volume = "19",
pages = "1014--22",
journal = "NAT MED",
issn = "1078-8956",
publisher = "NATURE PUBLISHING GROUP",
number = "8",

}

RIS

TY - JOUR

T1 - BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint

AU - Swaminathan, Srividya

AU - Huang, Chuanxin

AU - Geng, Huimin

AU - Chen, Zhengshan

AU - Harvey, Richard

AU - Kang, Huining

AU - Ng, Carina

AU - Titz, Björn

AU - Hurtz, Christian

AU - Sadiyah, Mohammed Firas

AU - Nowak, Daniel

AU - Thoennissen, Gabriela B

AU - Rand, Vikki

AU - Graeber, Thomas G

AU - Koeffler, H Phillip

AU - Carroll, William L

AU - Willman, Cheryl L

AU - Hall, Andrew G

AU - Igarashi, Kazuhiko

AU - Melnick, Ari

AU - Müschen, Markus

PY - 2013/8

Y1 - 2013/8

N2 - 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.

AB - 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.

KW - Animals

KW - B-Cell-Specific Activator Protein

KW - Basic-Leucine Zipper Transcription Factors

KW - Cell Death

KW - Cell Differentiation

KW - Cell Survival

KW - Cell Transformation, Neoplastic

KW - DNA-Binding Proteins

KW - Gene Deletion

KW - Gene Expression Regulation, Leukemic

KW - Green Fluorescent Proteins

KW - Immunoglobulin mu-Chains

KW - Mice

KW - Molecular Sequence Data

KW - Pre-B Cell Receptors

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma

KW - Precursor Cells, B-Lymphoid

KW - Proto-Oncogene Proteins c-myc

KW - RNA, Messenger

KW - STAT5 Transcription Factor

KW - Treatment Outcome

KW - Tumor Suppressor Protein p53

KW - V(D)J Recombination

U2 - 10.1038/nm.3247

DO - 10.1038/nm.3247

M3 - SCORING: Journal article

C2 - 23852341

VL - 19

SP - 1014

EP - 1022

JO - NAT MED

JF - NAT MED

SN - 1078-8956

IS - 8

ER -