Study reveals cause, potential precision therapies for aggressive type of lymphoma

DNA mutations are essential to the rapid development of an array of antibody-producing immune cells called B cells that collectively can recognize a vast number of specific targets. But this process can go awry in people with a mutation in a gene called SETD2, leading to a type of aggressive blood cancer, according to a study by Weill Cornell Medicine investigators.

The study, published April 20 in Cancer Discovery, found that having a mutation in one of the two copies of SETD2 in B cells can lead to a proliferation of cells that don’t readily repair their mutated DNA, causing an aggressive type of cancer called diffuse large B cell lymphoma (DLBCL).

“However, when both copies of this gene are mutated in the cancer cell, it is fatal to the cell, suggesting that drugs that target SETD2 might offer an effective treatment option for this type of lymphoma,” said senior author Dr. Ari Melnick, the Gebroe Family Professor of Hematology/Oncology in the Division of Hematology and Clinical Oncology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

Researchers have previously found that the SETD2 mutation disproportionately occurs in DLBCL in people of African ancestry.

“The finding points to a possible therapeutic intervention for these patients, who don’t otherwise have good options,” said Dr. Melnick. The strategy is now being tested in a phase 1 clinical trial.

Diffuse large B cell lymphoma develops in B cells in the lymph nodes of humans, dogs and some other mammals. To understand the underlying causes, lead author Dr. Wilfred Leung examined B cells of mice genetically engineered to lack one copy of SETD2. He began the study as a doctoral candidate in the laboratory of Dr. Kristy Richards, who was an associate professor with a joint appointment at the College of Veterinary Medicine at Cornell University and Weill Cornell Medicine. Her laboratory had studied cancer in humans and canines to accelerate the development of potential new treatments. Dr. Leung joined Dr. Melnick’s laboratory to complete the work after Dr. Richards died of breast cancer in 2019.

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