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SAB Member Leads Study Identifying Master Regulator Protein in B-Cell Lymphomas

A study led by an LRF Scientific Advisory Board (SAB) member suggests a new class of drug inhibitors may affect a broader range of lymphoma patients than originally thought.

A study led by an LRF Scientific Advisory Board (SAB) member suggests a new class of drug inhibitors may affect a broader range of lymphoma patients than originally thought. A collaborative team of researchers from institutions across the US and Canada, led by SAB member Ari Melnick, MD, of Weill Cornell Medical College, studied the EZH2 protein, believed to be a factor in a small subset of B-cell lymphomas when it exhibits mutations. Though EZH2 has been known for more than a decade, the role of both the normal and mutated protein in B-cell development has remained unknown. Dr. Melnick's study, which also involved contributions from fellow SAB member Randy Gascoyne of the British Columbia Cancer Agency, attempted to understand those roles.

The B-cells in which EZH2 is found produce antibodies against invading microbes. The researchers discovered that EZH2 is essential to the production of germinal center B-cells, which create the most powerful type of antibodies. Unfortunately, because germinal center B-cells divide quickly and mutate their antibody genes even under normal circumstances, they also tend to mutate other genes within their cells, which can cause cancer formation. EZH2 turns out to be the master regulator protein that both allows this rapid cell division and prevents it from stopping, or transitioning into antibody production. "Remarkably when EZH2 itself becomes mutated in certain ways, it locks B-cells into this proliferative and mutational state" said Dr. Melnick, "and in this way can help to trigger lymphoma formation." However, Dr. Melnick also noted, "even when EZH2 is not mutated it still plays a key role in maintaining the growth and survival of lymphomas derived from germinal center B-cells."

The EZH2 findings are significant because an EZH2 inhibitor drug was already under development, but originally believed to help only the small subset of patients who develop mutations in that gene. The researchers tested such an inhibitor against large panels of lymphoma cells and found particular success against germinal center-derived lymphomas, even those lacking an EZH2 mutation. The researchers' further discovery that EZH2 cooperates with BCL2 to drive these types of lymphomas, also suggests a combination therapy of inhibitors for both proteins will be even more effective. The study's results should ultimately lead the way to a new targeted therapy for a wide range of lymphomas.

More information on this study can be found at http://weill.cornell.edu/news/releases/wcmc/wcmc_2013/05_13_13.shtml.

June 2013