Public Release:  Study identifies drug resistance of CLL in bone marrow and lymph nodes

Potential mechanism identified

Dana-Farber Cancer Institute

ORLANDO --- In research to be presented at the American Society of Hematology (ASH) annual meeting, investigators at Dana-Farber Cancer Institute in Boston offer a new explanation of why chronic lymphocytic leukemia (CLL) tends to recur in the lymph nodes and bone marrow after being cleared from the bloodstream by chemotherapy. Their findings will be reported during in an oral session on Monday, Dec. 6, at 4:45 p.m. in room 315 of the Orange County Convention Center.

To uncover the reasons for CLL's resilience in the marrow and lymph nodes, the researchers employed a technique called BH3 profiling, which had been devised by senior author Anthony Letai, MD, PhD, and his Dana-Farber colleagues in 2005. The technique makes it possible to identify cancer cells that are less likely to undergo mitochondrial apoptosis (a form of programmed cell death involving cell structures called mitochondria) because of alterations in the Bcl-2 family of proteins. These abnormalities can make such cells less susceptible to both standard chemotherapy and novel, targeted agents.

In the current study, Letai and his associates found that when CLL cells from patients were grown with non-cancerous support cells from the bone marrow and lymph nodes, the CLL cells were more resistant to apoptosis - and hence harder to kill with treatment - than were CLL cells from the bloodstream. Using BH3 profiling, they discovered that although circulating CLL cells were likely to die by mitochondrial apoptosis in response to treatment, CLL cells grown among non-cancerous cells were much less likely to die this way. The presence of these normal cells, known as stroma, apparently helped the CLL cells survive, despite receiving treatment that would otherwise have resulted in their death.

"We hope that by clearly identifying the ability of stromal cells to reduce the CLL cells' capability to undergo apoptosis, we can exploit strategies to selectively target the 'help' that stromal cells give to CLL cells," says Letai.

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The study's lead author is Matthew Davids, MD, of Dana-Farber. Co-authors were Jennifer Brown, MD, PhD, of Dana-Farber, and Adrian Wiestner, MD, PhD, of the National Heart, Lung, and Blood Institute.

This study was supported by the NIH and Leukemia and Lymphoma Society.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women's Hospital as Dana-Farber/Brigham and Women's Cancer Center and it provides pediatric care with Children's Hospital Boston as Dana-Farber/Children's Hospital Cancer Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding.

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