Targeting EZH2 May Prevent Development of B-cell Lymphomas

A "master regulator" gene has been identified in immune system B-cell lymphocytes that when mutated fails to maintain the normal cell phenotype, which prompts the B-cells to enter a phase of uncontrolled cell division that results in the type of cancer known as B-cell lymphoma.

Most B-cell lymphomas arise from germinal center (GC) B-cells, since they divide rapidly while at the same time mutating their antibody genes. In some cases other genes become mutated as well, which can eventually result in lymphoma formation. GCs are sites within lymph nodes where mature B lymphocytes rapidly proliferate, differentiate, mutate their antibodies, and class switch their antibodies during a normal immune response to an infection. GCs are an important part of the B-cell humoral immune response, and they develop dynamically after the activation of B-cells by T-dependent antigen.

Investigators at Weill Cornell Medical College (New York, NY, USA) examined the role of the protein encoded by the EZH2 (enhancer of zeste homolog 2, also known as histone-lysine N-methyltransferase) gene, which is highly expressed in GC B-cells, in the process leading up to lymphoma formation.

They reported in the May 13, 2013, issue of the journal Cancer Cell that EZH2 repressed proliferation checkpoint genes and helped establish chromatin domains at key regulatory loci to transiently block the differentiation of B-cells away from the GC phenotype. Genomic deletion or pharmacologic suppression of EZH2 expression with a chemical inhibitor suppressed GC formation and function.

"EZH2 is a master regulator protein that turns off the brakes that prevent cell division, so it allows cells to divide without stopping," said senior author Dr. Ari Melnick, professor of medicine at Weill Cornell Medical College. "EZH2 prevents germinal cells from transitioning to antibody-secreting cells. Indeed, in the normal immune system EZH2 prevents B-cells from exiting germinal centers so that these cells can continue to undergo sustained rapid cell division, which continues until the immune system says to stop. Then EZH2 goes away, and B-cells can develop into antibody-secreting cells, which send antibodies into the circulation to fight off infection. Germinal center cells absolutely require EZH2 and the lymphomas that arise from germinal center cells inherit that need regardless of whether they have mutations."

"Researchers had thought EZH2 inhibitors would only help patients with a mutation in their EZH2 gene, which represents a small subset of lymphoma patients. What we found is that a majority of lymphomas turn out to be dependent on normal EZH2, not just mutated EZH2," said Dr. Melnick. "Our research indicates that these inhibitors will be remarkably effective. I am very optimistic."

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