EZH2 and BCL6 Cooperate to Assemble CBX8-BCOR Complex to Repress Bivalent Promoters, Mediate Germinal Center Formation and Lymphomagenesis

Wendy Béguelin; Matt Teater; Micah D Gearhart; María Teresa Calvo Fernández; Rebecca L. Goldstein; Mariano G. Cárdenas; Katerina Hatzi; Monica Rosen; Hao Shen; Connie M. Corcoran; Michelle Y. Hamline; Randy D. Gascoyne; Ross L. Levine; Omar Abdel-Wahab; Jonathan D. Licht; Rita Shaknovich; Olivier Elemento; Vivian J Bardwell; Ari M. Melnick

doi:10.1016/j.ccell.2016.07.006

EZH2 and BCL6 Cooperate to Assemble CBX8-BCOR Complex to Repress Bivalent Promoters, Mediate Germinal Center Formation and Lymphomagenesis

Wendy Béguelin, Matt Teater, Micah D Gearhart, María Teresa Calvo Fernández, Rebecca L. Goldstein, Mariano G. Cárdenas, Katerina Hatzi, Monica Rosen, Hao Shen, Connie M. Corcoran, Michelle Y. Hamline, Randy D. Gascoyne, Ross L. Levine, Omar Abdel-Wahab, Jonathan D. Licht, Rita Shaknovich, Olivier Elemento, Vivian J Bardwell, Ari M. Melnick

Genetics, Cell Biology and Development (TMED)

Research output: Contribution to journal › Article › peer-review

192 Scopus citations

Abstract

The EZH2 histone methyltransferase mediates the humoral immune response and drives lymphomagenesis through formation of bivalent chromatin domains at critical germinal center (GC) B cell promoters. Herein we show that the actions of EZH2 in driving GC formation and lymphoma precursor lesions require site-specific binding by the BCL6 transcriptional repressor and the presence of a non-canonical PRC1-BCOR-CBX8 complex. The chromodomain protein CBX8 is induced in GC B cells, binds to H3K27me3 at bivalent promoters, and is required for stable association of the complex and the resulting histone modifications. Moreover, oncogenic BCL6 and EZH2 cooperate to accelerate diffuse large B cell lymphoma (DLBCL) development and combinatorial targeting of these repressors results in enhanced anti-lymphoma activity in DLBCLs.

Original language	English (US)
Pages (from-to)	197-213
Number of pages	17
Journal	Cancer Cell
Volume	30
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2016.07.006
State	Published - Aug 8 2016

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Publisher Copyright:
© 2016 Elsevier Inc.

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Béguelin, W., Teater, M., Gearhart, M. D., Calvo Fernández, M. T., Goldstein, R. L., Cárdenas, M. G., Hatzi, K., Rosen, M., Shen, H., Corcoran, C. M., Hamline, M. Y., Gascoyne, R. D., Levine, R. L., Abdel-Wahab, O., Licht, J. D., Shaknovich, R., Elemento, O., Bardwell, V. J., & Melnick, A. M. (2016). EZH2 and BCL6 Cooperate to Assemble CBX8-BCOR Complex to Repress Bivalent Promoters, Mediate Germinal Center Formation and Lymphomagenesis. Cancer Cell, 30(2), 197-213. https://doi.org/10.1016/j.ccell.2016.07.006

Béguelin, W, Teater, M, Gearhart, MD, Calvo Fernández, MT, Goldstein, RL, Cárdenas, MG, Hatzi, K, Rosen, M, Shen, H, Corcoran, CM, Hamline, MY, Gascoyne, RD, Levine, RL, Abdel-Wahab, O, Licht, JD, Shaknovich, R, Elemento, O, Bardwell, VJ & Melnick, AM 2016, 'EZH2 and BCL6 Cooperate to Assemble CBX8-BCOR Complex to Repress Bivalent Promoters, Mediate Germinal Center Formation and Lymphomagenesis', Cancer Cell, vol. 30, no. 2, pp. 197-213. https://doi.org/10.1016/j.ccell.2016.07.006

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abstract = "The EZH2 histone methyltransferase mediates the humoral immune response and drives lymphomagenesis through formation of bivalent chromatin domains at critical germinal center (GC) B cell promoters. Herein we show that the actions of EZH2 in driving GC formation and lymphoma precursor lesions require site-specific binding by the BCL6 transcriptional repressor and the presence of a non-canonical PRC1-BCOR-CBX8 complex. The chromodomain protein CBX8 is induced in GC B cells, binds to H3K27me3 at bivalent promoters, and is required for stable association of the complex and the resulting histone modifications. Moreover, oncogenic BCL6 and EZH2 cooperate to accelerate diffuse large B cell lymphoma (DLBCL) development and combinatorial targeting of these repressors results in enhanced anti-lymphoma activity in DLBCLs.",

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doi = "10.1016/j.ccell.2016.07.006",

language = "English (US)",

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AU - Calvo Fernández, María Teresa

AU - Goldstein, Rebecca L.

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AU - Rosen, Monica

AU - Shen, Hao

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AU - Hamline, Michelle Y.

AU - Gascoyne, Randy D.

AU - Levine, Ross L.

AU - Abdel-Wahab, Omar

AU - Licht, Jonathan D.

AU - Shaknovich, Rita

AU - Elemento, Olivier

AU - Bardwell, Vivian J

AU - Melnick, Ari M.

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AB - The EZH2 histone methyltransferase mediates the humoral immune response and drives lymphomagenesis through formation of bivalent chromatin domains at critical germinal center (GC) B cell promoters. Herein we show that the actions of EZH2 in driving GC formation and lymphoma precursor lesions require site-specific binding by the BCL6 transcriptional repressor and the presence of a non-canonical PRC1-BCOR-CBX8 complex. The chromodomain protein CBX8 is induced in GC B cells, binds to H3K27me3 at bivalent promoters, and is required for stable association of the complex and the resulting histone modifications. Moreover, oncogenic BCL6 and EZH2 cooperate to accelerate diffuse large B cell lymphoma (DLBCL) development and combinatorial targeting of these repressors results in enhanced anti-lymphoma activity in DLBCLs.

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EZH2 and BCL6 Cooperate to Assemble CBX8-BCOR Complex to Repress Bivalent Promoters, Mediate Germinal Center Formation and Lymphomagenesis

Abstract

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