January 25, 2010

Mutations Contribute to Type of Non-Hodgkin Lymphoma

Cell with small red spots on surface. Red clusters of B cell receptors (BCRs) dot the surface of only the ABC subtype of diffuse large B-cell lymphomas. Ongoing BCR signaling lets these cancer cells survive. Dr. Louis M. Staudt, NCI.

Researchers have discovered genetic mutations that may contribute to the development of an aggressive form of non-Hodgkin lymphoma—a cancer of white blood cells. The findings provide insight into a mechanism that cancer cells may use to survive, and highlight potential new treatment targets.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma, representing about 30% of newly diagnosed cases. DLBCL originates in B cells, which are antibody-producing immune cells and one of the body's key defense mechanisms. Subtypes of DLBCL vary biologically and differ in how patients respond to chemotherapy. The activated B cell-like (ABC) subtype is the least responsive to currently available therapies.

Previous research suggested that a process called BCR signaling might contribute to the development of lymphomas. When B cells encounter a piece of a virus or other foreign substance, proteins on the cell surface known as B cell receptors (BCRs) activate a stepwise series of biochemical events—called a signaling pathway—that tells the cell to survive and proliferate. Researchers at NIH's National Cancer Institute (NCI), National Institute for Allergy and Infectious Diseases (NIAID) and National Human Genome Research Institute (NHGRI) and their colleagues set out to explore the role of BCR signaling in ABC subtype lymphomas.

The researchers reported on January 7, 2010, in Nature that they identified critical points in the BCR signaling pathway that affect the survival of lymphoma cells. Interfering with several components of the pathway caused lymphoma cells to die. Thus, ongoing BCR signaling is necessary for ABC subtype DLBCL cells to survive.

The team then looked for mutations in genes that encode these signaling pathway components in human DLBCL tumors. About one-fifth of ABC subtype tumors, they found, had a critical mutation in a BCR signaling component known as CD79B. The mutation increased BCR signaling by raising the amount of BCRs on the cell surface and by blocking a process that normally turns off the pathway.

The team tested dasatinib, a drug that is approved for the treatment of chronic myelogenous leukemia in ABC subtype DLBCL cells. They found that the drug turned off BCR signaling by inhibiting the activity of one of the pathway's components, thereby killing the cells.

"Our data provide important evidence that BCR signaling plays a crucial role in ABC DLBCL," says study senior author Dr. Louis M. Staudt of NCI. The results suggest new therapeutic opportunities for ABC subtype lymphoma.

More research will be needed to understand how chronic, active BCR signaling begins. "Tests will also need to be developed that can identify patients with cases of DLBCL that depend on chronic, active BCR signaling, so that we can rationally develop clinical trials with agents that inhibit the BCR pathway," Staudt says.

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