Gene mutations reveal potential new targets for non-Hodgkin’s treatment

A group of researchers have discovered genetic mutations that may contribute to the development of an aggressive form of non- Hodgkin\'s lymphoma.

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A group of researchers have discovered genetic mutations that may contribute to the development of an aggressive form of non-Hodgkin's lymphoma.

These findings provide insight into a mechanism that cancer cells may use to survive, thus identifying potential new targets for treatment of the disease. The study conducted by researchers at the National Cancer Institute (NCI), the National Institute for Allergy and Infectious Diseases, and the National Human Genome Research Institute—all components of the National Institutes of Health—and colleagues appeared in January in Nature.

"Our data provide important evidence that BCR signaling plays a crucial role in ABC DLBCL [activated B cell-like diffuse large B-cell lymphoma]," says study senior author Dr. Louis M. Staudt of NCI's Center for Cancer Research. "As such, this study opens up a wealth of therapeutic opportunities for this type of lymphoma and may eventually lead to clinical trials testing agents that target components of the BCR signaling pathway."

Staudt's laboratory studies the molecular pathogenesis of human lymphoid malignancies and has three primary goals: to establish a new molecular diagnosis of human lymphoid malignancies using gene expression profiling, to elucidate the oncogenic pathways that result in malignant transformation of normal B lymphocytes, and to identify molecular targets for development of novel therapeutics for these cancers.

"Our laboratory uses functional genomics, chemical genetics and molecular biological techniques to identify new molecular targets for therapy of lymphoid malignancies," Staudt says on his Web page. "Some of the genes that are associated with clinical prognosis have provided new molecular targets. For example, our laboratory discovered that the subgroup of DLBCL with the worst prognosis relies on constitutive activity of the NF-kB signaling pathway for survival; molecular or pharmacological inhibition of this pathway kills this type of lymphoma."

As part of its work, Staudt's laboratory has created a library of more than 10,000 retroviruses that can inducibly express small hairpin RNAs (shRNAs) targeting more than 3,000 human genes. When expressed in a cell, each shRNA can be processed into a small interfering RNA that can decrease the mRNA expression of a single human gene.

"We are using this library to identify genes that are important for the proliferation and survival of lymphoma cells," Staudt says.

Staudt's team found that dasatinib, a drug that is approved for the treatment of chronic myelogenous leukemia, could turn off BCR signaling by inhibiting the activity of one of the pathway's components, a protein called BTK, thereby killing ABC subtype DLBCL cells that exhibit chronic active BCR signaling.

Diffuse large B-cell lymphoma (DLBCL) originates in B cells, which are antibody-producing immune cells and one of the body's key defense mechanisms. DLBCL is the most common form of non-Hodgkin's lymphoma and represents about 30 percent of newly diagnosed cases. There are different subtypes of DLBCL that vary biologically and differ significantly in their rates of patient survival following chemotherapy. The activated B cell-like (ABC) subtype is the least responsive to currently available therapies.

When a normal B cell encounters a foreign substance, proteins on the cell surface known as B cell receptors (BCR) activate signaling pathways that tell the cell to survive and proliferate. A signaling pathway is a stepwise series of biochemical events that help regulate important cellular functions, such as proliferation and survival. Each pathway contains points at which normal signaling can become altered, causing cells to function abnormally. Alterations in signaling pathways have been found in many types of cancer cells. Previous research had suggested that BCR signaling might contribute to the development of lymphomas; however, direct genetic and functional evidence was lacking.

In the new study, researchers first used advanced laboratory techniques to identify critical points in the BCR signaling pathway that affect the survival of lymphoma cells. They found that interference with several individual components of this pathway caused lymphoma cells to die. Thus, ongoing BCR signaling—which the authors refer to as chronic active signaling—is necessary for ABC subtype DLBCL cell survival.

The team then looked for mutations in genes that encode these signaling pathway components in human DLBCL tumors. They found that about one-fifth of ABC subtype tumors had mutations in a BCR signaling component known as CD79B. The mutations increased BCR signaling by blocking a braking process that normally turns off the pathway in response to inhibitory signals.

Staudt points out that more research is needed to understand the various biochemical mechanisms by which 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 adds.

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