Mutant protein implicated in diffuse Large B-cell lymphoma
(13 May 2009: VIDYYA MEDICAL NEWS SERVICE) -- Recent studies have implicated the NF-?B signaling pathway in the development of a subset of diffuse large B-cell lymphomas. Two new studies now provide another piece of the puzzle. While mutations in genes such as CARD11 can spur cell growth by activating the NF-?B pathway, mutations in a gene called A20 may remove a natural "brake" on the pathway. The findings suggest that multiple lesions in the NF-?B pathway may be involved in DLBCL, the most common lymphoma in adults, according to results published online in Nature this week.
"We have identified genetic lesions that target multiple components of the same pathway in the majority of DLBCL with constitutive activation of NF-?B, and this will have implications for the possible design of therapies that may benefit patients with these abnormalities," said Dr. Laura Pasqualucci of the Herbert Irving Comprehensive Cancer Center at Columbia University, who led one of the studies. Drugs targeting the NF-?B pathway are in development, she noted.
Her team analyzed tumor samples from 168 cases of DLBCL. Mutations in multiple genes associated with the NF-?B pathway were found in half of the activated B-cell-like (ABC) subtypes analyzed, and in a smaller fraction of the germinal center B-cell-like (GBC) subtypes. The A20 gene was the most commonly altered, with a third of the ABC-DLBCL patients showing inactivation of both gene copies by mutation or deletion.
In the second study, researchers at the University of Tokyo conducted genome-wide analyses of genetic lesions in 238 B-cell lymphomas. The A20 protein was frequently inactivated in several types of cancer, including mucosa-associated tissue lymphoma, a form of Hodgkin's lymphoma, and to a lesser extent, B-cell lymphomas. Both teams found that, in laboratory experiments, the normal A20 protein suppressed cell growth and caused abnormal cells to commit suicide when reintroduced into A20-deficient cells.
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