AACR 2014: How deregulation of histone methyltransferases drive malignant transformation of B-cells

wendybeguelinBy Wendy Béguelin, PhD

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, thus generating a diverse set of clones of cells encoding high affinity antibodies. The GC phenotype poses a significant risk in the malignant transformation to B cells, with epigenetic regulatory complexes playing a critical role in lymphomagenesis. During a symposium session at the recent American Association for Cancer Research, the Melnick Lab, reported how the deregulation of histone methyltransferases causes the malignant transformation of B-cells.

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 GC, and GC B cells display cytosine methylation redistribution as compared to resting or naïve B cells. DLBCL 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 outcomes in B-cell lymphoma. This suggests 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 allows for a more complete response to chemotherapy treatment. These DNA methyltransferase inhibitors can be safely combined with standard lymphoma therapies for first line treatment of patients with DLBCL. However, further research will be required to confirm this targeted therapy approach for clinical use in patients.

Author: lymphomaprogram

Located on the Upper East Side of New York City, the Lymphoma Program at Weill Cornell Medical College/NewYork Presbyterian Hospital is internationally recognized for our efforts to enable patients with non-Hodgkin lymphoma, Hodgkin disease and related disorders to have the best possible clinical outcome, including cure when possible.

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