Abstract SY09-03: How deregulation of histone methyltransferases drive malignant transformation of B-cells

Diffuse Large B-cell Lymphomas (DLBCLs) are a heterogeneous group of diseases initiating from germinal center (GC) B cells. GC B cells are uniquely specialized to tolerate rapid proliferation, and physiological genomic instability in order to generate a diverse set of clones of cells encoding high affinity antibodies. This accelerated micro-evolutionary process requires the concerted action of transcription and epigenetic factors that collectively reprogram B cells to overcome many of their normal checkpoint restraints and tolerate the various stresses associated with affinity maturation. The GC phenotype poses a significant risk of malignant transformation to B cells, which must accordingly balance suppression of checkpoints with suppression of pro-oncogenic genes. Epigenetic regulatory complexes play a critical role in lymphomagenesis. EZH2, which epigenetically silences genes through histone 3 lysine 27 methylation is upregulated in normal and malignant GC B cells. EZH2 is often affected by gain of function mutations in lymphomas that alter its enzymatic specificity. EZH2 mediates GC formation by transiently suppressing checkpoint genes and terminal differentiation genes through formation of bivalent chromatin domains. EZH2 somatic mutations induce germinal center hyperplasia and malignant transformation, and cooperate with other oncogenes such as BCL2. EZH2 specific inhibitors can suppress the growth of GC derived lymphoma cells in vitro and in vivo, and are currently being evaluated in early phase clinical trials. DNA methyltransferase 1 (DNMT1) is required for B cells to form GCs, and GC B cells display cytosine methylation redistribution as compared to resting or naïve B cells. DLBCLs in turn exhibit prominent and heterogeneous disruption of cytosine methylation distribution, with specific and distinct DNA methylation profiles occurring in different lymphoma subtypes. Epigenetic heterogeneity is associated with unfavorable outcome in B-cell lymphomas, suggesting that epigenetic diversity may provide a survival advantage to lymphoma cell populations. DNA methyltransferase inhibitors can reprogram lymphoma cells to develop a form of incomplete senescence that sensitizes lymphoma cells to more readily respond to chemotherapy. DNA methyltransferase inhibitors can be safely combined with standard lymphoma therapies for the up-front treatment of patients with high-risk lymphomas. Citation Format: Wendy Beguelin, Matt Teater, Relja Popovic, Yanwen Jiang, Leandro Cerchietti, Rita Shaknovich, Randy Gascoyne, Ross Levine, Omar Abdel-Wahab, Jonathan Licht, Olivier Elemento, Ari M. Melnick. How deregulation of histone methyltransferases drive malignant transformation of B-cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY09-03. doi:10.1158/1538-7445.AM2014-SY09-03