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

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189 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
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 - 8 Aug 2016
Externally published	Yes

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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

@article{a9c5bca76faa41e082dc7cf0559e538a,

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

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.",

author = "Wendy B{\'e}guelin and Matt Teater and Gearhart, {Micah D.} and {Calvo Fern{\'a}ndez}, {Mar{\'i}a Teresa} and Goldstein, {Rebecca L.} and C{\'a}rdenas, {Mariano G.} and Katerina Hatzi and Monica Rosen and Hao Shen and Corcoran, {Connie M.} and Hamline, {Michelle Y.} and Gascoyne, {Randy D.} and Levine, {Ross L.} and Omar Abdel-Wahab and Licht, {Jonathan D.} and Rita Shaknovich and Olivier Elemento and Bardwell, {Vivian J.} and Melnick, {Ari M.}",

note = "Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = aug,

day = "8",

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

language = "English",

volume = "30",

pages = "197--213",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

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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

TY - JOUR

T1 - EZH2 and BCL6 Cooperate to Assemble CBX8-BCOR Complex to Repress Bivalent Promoters, Mediate Germinal Center Formation and Lymphomagenesis

AU - Béguelin, Wendy

AU - Teater, Matt

AU - Gearhart, Micah D.

AU - Calvo Fernández, María Teresa

AU - Goldstein, Rebecca L.

AU - Cárdenas, Mariano G.

AU - Hatzi, Katerina

AU - Rosen, Monica

AU - Shen, Hao

AU - Corcoran, Connie M.

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.

PY - 2016/8/8

Y1 - 2016/8/8

N2 - 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.

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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DO - 10.1016/j.ccell.2016.07.006

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AN - SCOPUS:84989961535

SN - 1535-6108

VL - 30

SP - 197

EP - 213

JO - Cancer Cell

JF - Cancer Cell

IS - 2

ER -

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

Abstract

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