March 17, 2008

Coiled Protein Region May Play Role in Non-Hodgkin Lymphoma

Drawing of a coiled ribbon structure. Illustration of a coiled-coil protein domain. Research Collaboratory for Structural Bioinformatics Protein Data Bank.

Genetic mutations found in patients who have an especially deadly form of non-Hodgkin lymphoma have led researchers to a better understanding of how the cancer develops and how it might be treated.

Diffuse large B-cell lymphoma (DLBCL), a cancer that originates in white blood cells called B lymphocytes, is the most common form of non-Hodgkin lymphoma, accounting for 30-40% of cases. DLBCL can affect people of any age, but is most common in adults 60 years or older. Roughly half of DLBCLs are curable by current therapies. How well people respond to these therapies has been traced to molecular differences in the tumors. The least curable subtype of DLBCL is called ABC DLBCL.

Previous studies by researchers at NIH’s National Cancer Institute (NCI) showed that the malignant cells of the hard-to-treat ABC subtype rely on a series of molecular events involving a protein called CARD11. CARD11 abnormally stimulates a molecular pathway called the NF-kB signaling pathway in the ABC subtype, NCI researchers found, but not in a more easily treated subtype.

In the current study, NCI scientists and their colleagues examined the sequence of the CARD11 gene in 16 ABC DLBCL biopsy specimens and 4 ABC DLBCL laboratory cell lines. As they reported in the March 6, 2008, issue of Science, they discovered mutations in 3 of the biopsy specimens and 1 cell line. All the mutations seemed to affect a small segment of the CARD11 protein known as the coiled-coil domain, which is required for proper CARD11 function.

The researchers next sequenced the coiled-coil domain in 136 additional DLBCL biopsy specimens. They detected mutations altering the area in or near this coiled-coil region in about 10% of ABC specimens but in only about 4% of specimens from another DLBCL subtype.

The researchers tested the mutant CARD11 proteins in other cell lines and found that the proteins spontaneously activated the NF-kB signaling pathway, thereby promoting the survival of malignant cells. The scientists also discovered that they were able to kill ABC DLBCL cells in the laboratory by genetically interfering with the function of the CARD11 coiled-coil domain.

These results suggest that the coiled-coil domain of CARD11 is a promising target for the development of drugs to treat ABC DLBCL. “Our results demonstrate that CARD11 is a bona fide cancer-causing gene in DLBCL, thus providing a genetic rationale for the development of drugs that could block the CARD11 pathway,” said lead investigator Dr. Louis Staudt of NCI's Center of Cancer Research.

Related Links