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 C.; Kang, Huining; Ng, Carina; Titz, Bjoern; 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

doi:10.1038/nm.3247

Cited by 103 publications

(117 citation statements)

References 26 publications

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“…7E). In this context, it seems relevant that adult Ph + ALL (39) and childhood pre-B ALL (40) are characterized by frequent genetic lesions in B-cell lineage transcriptions factors (IKZF1, PAX5, EBF1, and BACH2) (27) (Fig. 2, S6) on XBP1 expression and activity.…”

Section: Plasma Cell-specific Gene Expression As a Results Of Genetic mentioning

confidence: 99%

“…We performed transfections of retroviral constructs and their corresponding empty vector controls (SI Appendix, Table S5) as previously described (26,27). A detailed description is given in SI Appendix, Supplemental Material and Methods.…”

Section: Methodsmentioning

confidence: 99%

“…S3 B and C). De novo expression of Ig μ-heavy chains results in rapid down-regulation of Xbp1-s in parallel with up-regulation of its transcriptional repressors Bach2 (27) and BCL6 (28) (13) and NRAS G12D to model RAS-driven childhood ALL (14).…”

Section: In Vitro In Vivomentioning

confidence: 99%

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Mechanistic rationale for targeting the unfolded protein response in pre-B acute lymphoblastic leukemia

Masouleh¹,

Geng²,

Hurtz³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The unfolded protein response (UPR) pathway, a stress-induced signaling cascade emanating from the endoplasmic reticulum (ER), regulates the expression and activity of molecules including BiP (HSPA5), IRE1 (ERN1), Blimp-1 (PRDM1), and X-box binding protein 1 (XBP1). These molecules are required for terminal differentiation of B cells into plasma cells and expressed at high levels in plasma cell-derived multiple myeloma. Although these molecules have no known role at early stages of B-cell development, here we show that their expression transiently peaks at the pre-B-cell receptor checkpoint. Inducible, Cre-mediated deletion of Hspa5, Prdm1, and Xbp1 consistently induces cellular stress and cell death in normal pre-B cells and in pre-B-cell acute lymphoblastic leukemia (ALL) driven by BCR-ABL1-and NRAS G12D oncogenes. Mechanistically, expression and activity of the UPR downstream effector XBP1 is regulated positively by STAT5 and negatively by the B-cellspecific transcriptional repressors BACH2 and BCL6. In two clinical trials for children and adults with ALL, high XBP1 mRNA levels at the time of diagnosis predicted poor outcome. A small molecule inhibitor of ERN1-mediated XBP1 activation induced selective cell death of patient-derived pre-B ALL cells in vitro and significantly prolonged survival of transplant recipient mice in vivo. Collectively, these studies reveal that pre-B ALL cells are uniquely vulnerable to ER stress and identify the UPR pathway and its downstream effector XBP1 as novel therapeutic targets to overcome drug resistance in pre-B ALL.

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Section: Plasma Cell-specific Gene Expression As a Results Of Genetic mentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Mechanistic rationale for targeting the unfolded protein response in pre-B acute lymphoblastic leukemia

Masouleh¹,

Geng²,

Hurtz³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition to SHM and CSR, Bach2 has been shown to regulate the early stage of B cell development (Swaminathan et al 2013). Upon the recombination of the V-D-J region of the immu- noglobulin heavy chain gene, pre-B cells with successful rearrangement become quiescent, while those with nonproductive rearrangement are eliminated.…”

Section: Bach2 Function In the Pre-b Cell Stagementioning

confidence: 99%

Wearing Red for Signaling: The Heme-Bach Axis in Heme Metabolism, Oxidative Stress Response and Iron Immunology

Igarashi

Watanabe-Matsui

2014

Tohoku J. Exp. Med.

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The connection between gene regulation and metabolism is an old issue that warrants revisiting in order to understand both normal as well as pathogenic processes in higher eukaryotes. Metabolites affect the gene expression by either binding to transcription factors or serving as donors for post-translational modification, such as that involving acetylation and methylation. The focus of this review is heme, a prosthetic group of proteins that includes hemoglobin and cytochromes. Heme has been shown to bind to several transcription factors, including Bach1 and Bach2, in higher eukaryotes. Heme inhibits the transcriptional repressor activity of Bach1, resulting in the derepression of its target genes, such as globin in erythroid cells and heme oxygenase-1 in diverse cell types. Since Bach2 is important for class switch recombination and somatic hypermutation of immunoglobulin genes as well as regulatory and effector T cell differentiation and the macrophage function, the heme-Bach2 axis may regulate the immune response as a signaling cascade. We discuss future issues regarding the topic of the iron/heme-gene regulation network based on current understanding of the heme-Bach axis, including the concept of "iron immunology" as the synthesis of the iron metabolism and the immune response.

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“…Bach2 plays a critical role in negative selection (i.e. elimination of cells unsuccessful in the rearrangement) at the pre-BCR checkpoint (6). In mature B cells, Bach2 is required for the class switch recombination (CSR) and somatic hypermutation that diversify the effector function and antigen affinity, respectively, of antibody molecules in response to antigen and other stimulation (7).…”

mentioning

confidence: 99%

The Transcription Factor Bach2 Is Phosphorylated at Multiple Sites in Murine B Cells but a Single Site Prevents Its Nuclear Localization

Ando¹,

Shima

Tamahara

et al. 2016

Journal of Biological Chemistry

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2), and Irf (3) families have been well studied in the context of the immune system in part due to their clear and established association with the upstream signaling cascades. In contrast, although the phosphatidylinositol 3-kinase (PI3K) pathway is critically important for the regulation of immune cells, its downstream transcription factors are still unclear except for the Foxo family (4). In this study, we investigated the possibility that the transcription factor Bach2 might be regulated in B cells by the PI3K pathway. Salient features of Bach2 relevant to this study are as follows.Bach2 regulates the immune cells at multiple points. During the development of B cells from the progenitor cells, Bach2, together with its related factor Bach1, represses the expression of myeloid genes. The repression of the myeloid program is critical for the progenitor cells to be committed to the B cell fate (5). At the stage of pre-B cells, the successful completion of antibody heavy chain gene rearrangement is monitored by the lack or presence of pre-B cell receptor (pre-BCR 2 checkpoint). Bach2 plays a critical role in negative selection (i.e. elimination of cells unsuccessful in the rearrangement) at the pre-BCR checkpoint (6). In mature B cells, Bach2 is required for the class switch recombination (CSR) and somatic hypermutation that diversify the effector function and antigen affinity, respectively, of antibody molecules in response to antigen and other stimulation (7). Bach2 promotes CSR by delaying the expression of Blimp-1, the master regulator of plasma cell differentiation, and thereby securing a time window for CSR before the terminal differentiation to plasma cells (8 -10). A reduction in the Bach2 expression in memory B cells is involved in their rapid plasma cell differentiation upon antigen re-exposure (11). An integral view of the Bach2 functions in B cells has been proposed as a gene regulatory network (GRN) consisting of Bach2 and other * This work was supported by Grants-in-aid 15H02506, 25670156, 24390066, 23116003, 21249014, 17054028, and 25291042

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

Cited by 103 publications

References 26 publications

Mechanistic rationale for targeting the unfolded protein response in pre-B acute lymphoblastic leukemia

Mechanistic rationale for targeting the unfolded protein response in pre-B acute lymphoblastic leukemia

Wearing Red for Signaling: The Heme-Bach Axis in Heme Metabolism, Oxidative Stress Response and Iron Immunology

The Transcription Factor Bach2 Is Phosphorylated at Multiple Sites in Murine B Cells but a Single Site Prevents Its Nuclear Localization

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