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Keck Team spies Gene Transformation Linked to Non-hodgkin s Lymphoma

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A team of researchers from the University of Southern California have identified a genetic transformation in lymphocytic chromosomes that may cause cells to develop a form of non-Hodgkin’s lymphoma.

Lead author Michael Lieber, a scientist at the Keck School of Medicine and a professor of pathology and biochemistry, said the “fragile” site his team identified is located on the Bcl-2 gene on chromosome 18. Lieber said the Bcl-2 gene, which plays a role in blocking apoptosis, is “the most common fragile site in all of cancer.”

“That one break site, which is only about 120 base pairs long, is responsible for 4 percent of all cancers,” he said in his group’s study, which appears in the March 4 issue of Nature.

According to Lieber, before it can trigger follicular lymphoma, the Bcl-2 gene must first undergo a 14;18 translocation. “Of all the chromosomal fragile sites in cancer, this is the first one where we’ve actually understood why it’s fragile,” Lieber said.

Lieber said his team’s discovery came about after researchers from USC/Norris laboratory developed what he calls “the bisulfide method.” The technique is predicated on treating DNA with bisulfide, which causes the cytosine bases in the sample to “undergo a transformation” — but only if they exist in a single-stranded region. If they are in the normal double-stranded configuration, they are spared the transformation, Lieber said. “So this has allowed us to pinpoint areas of DNA that are not arranged in a double helix and to explore them.”

To be sure, Lieber is not certain if his team’s discovery has any potential clinical implications: “It’s important to know how and why cancer begins,” he said in a statement released by the Keck School. “And this is an important step to understanding that — to understanding why the break is happening and why the chromosomes are swapping arms.

“We already knew that this translocation throttles the Bcl-2 up, making the cell invincible — and making it a good cancer cell,” Lieber added in the statement. “But nobody knew why it was happening. Now we are beginning to understand.”

Sathees Chukkurumbal Raghavan, a research associate in Lieber’s lab and the paper’s first author, said: “While we know it deviates from the standard helix, we don’t know what the base pairing is at the fragile site.”

Follicular lymphoma is the second-most common form of non-Hodgkin’s lymphoma, with somewhere between 13,000 and 22,000 cases being diagnosed each year, generally in older individuals. The five-year survival rate is around 75 percent.

— KL

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