A majority of B-cell lymphomas arise from germinal center (GC) B-cells including diffuse large B-cell lymphomas (DLBCL) and follicular lymphomas (FL). GCs are transient structures that form in response to T- cell dependent antigen exposure within which B-cells undergo proliferation and somatic hypermutation. We find that the H3K27 histone methyltransferase EZH2 is required for normal B-cells to form GCs. EZH2 plays a dual role in GC B-cells by suppressing proliferation checkpoint genes and genes required for B-cells to exit the GC reaction. EZH2 is widely expressed in DLBCL and FL, but a subset of these tumors acquire EZH2 point mutations which enable this enzyme to more efficiently trimethylate H3K27. Mutant EZH2 induces greater promoter H3K27me3 and more profound silencing of EZH2 targets, resulting in sustained proliferation and differentiation blockade. Therapeutic targeting of EZH2 is now possible thanks to the development of specific small molecule inhibitors. These drugs suppress DLBCL and FL cell lines with both mutant and WT EZH2, suggesting that EZH2 dependence may reflect a GC lineage role of EZH2. However, response to EZH2 inhibitors occurs slowly, likely reflecting the kinetics of reversal of epigenetic silencin. We hypothesize that EZH2 targeted therapy will be effective against DLBCL and FL with specific genetic and epigenetic features. We predict that resistance to these agents may occur due to their slow response kinetics. We hypothesize that EZH2 inhibitors will synergize with standard and experimental anti-lymphoma agents targeting complementary genetically and epigenetically defined pathways, but require rationale studies to achieve optimal combinatorial potency. Hence our proposal will explore the genetic and epigenetic determinants linked to EZH2 dependency in DLBCL and FL patients, will identify mechanisms through which acquired resistance might develop to EZH2 inhibitors, and the optimal manner in which these drugs could be combined with other anti-lymphoma drugs. Finally we will perform state of the art correlative studies in the context of the first in man clinical trial of a potent EZH2 inhibitor for DLBCL patients to validate the pharmacodynamics and tumor background of lymphomas susceptible of EZH2 inhibitors in humans.

Public Health Relevance

Human GC derived lymphomas are largely biological dependent on the EZH2 polycomb protein. Our proposal will take advantage of this finding to translate a novel form of epigenetic targeted therapy to the clinical targeting EZH2 and its effects on chromatin including silencing of bivalent promoters linked to B-cell proliferation and differentiation.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Arya, Suresh
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Weill Medical College of Cornell University
Internal Medicine/Medicine
Schools of Medicine
New York
United States
Zip Code
Purwada, Alberto; Shah, Shivem B; Béguelin, Wendy et al. (2018) Ex vivo synthetic immune tissues with T cell signals for differentiating antigen-specific, high affinity germinal center B cells. Biomaterials :
Dominguez, Pilar M; Ghamlouch, Hussein; Rosikiewicz, Wojciech et al. (2018) TET2 Deficiency Causes Germinal Center Hyperplasia, Impairs Plasma Cell Differentiation, and Promotes B-cell Lymphomagenesis. Cancer Discov 8:1632-1653
Béguelin, Wendy; Rivas, Martín A; Calvo Fernández, María T et al. (2017) EZH2 enables germinal centre formation through epigenetic silencing of CDKN1A and an Rb-E2F1 feedback loop. Nat Commun 8:877
Jiang, Yanwen; Ortega-Molina, Ana; Geng, Huimin et al. (2017) CREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas. Cancer Discov 7:38-53
Oricchio, Elisa; Katanayeva, Natalya; Donaldson, Maria Christine et al. (2017) Genetic and epigenetic inactivation of SESTRIN1 controls mTORC1 and response to EZH2 inhibition in follicular lymphoma. Sci Transl Med 9:
Cardenas, Mariano G; Oswald, Erin; Yu, Wenbo et al. (2017) The Expanding Role of the BCL6 Oncoprotein as a Cancer Therapeutic Target. Clin Cancer Res 23:885-893
Bunting, Karen L; Soong, T David; Singh, Rajat et al. (2016) Multi-tiered Reorganization of the Genome during B Cell Affinity Maturation Anchored by a Germinal Center-Specific Locus Control Region. Immunity 45:497-512
Béguelin, Wendy; Teater, Matt; Gearhart, Micah D et al. (2016) EZH2 and BCL6 Cooperate to Assemble CBX8-BCOR Complex to Repress Bivalent Promoters, Mediate Germinal Center Formation and Lymphomagenesis. Cancer Cell 30:197-213
Jiang, Yanwen; Dominguez, Pilar M; Melnick, Ari M (2016) The many layers of epigenetic dysfunction in B-cell lymphomas. Curr Opin Hematol 23:377-84
LaFave, Lindsay M; Béguelin, Wendy; Koche, Richard et al. (2015) Loss of BAP1 function leads to EZH2-dependent transformation. Nat Med 21:1344-9

Showing the most recent 10 out of 13 publications