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7.01.2013

New Strategy for Treating Leukemia Reported in Nature

A groundbreaking laboratory study indicates that blocking the formation of a cancer-causing protein complex in blood cells could treat a deadly type of leukemia in children and adults.

“By shedding new light on the protein-to-protein interactions that lead to acute myeloid leukemia (AML), our study points to a potential therapeutic strategy,” said Stephen D. Nimer, M.D., Director of the Sylvester Comprehensive Cancer Center. He is a co-author of the collaborative multicenter study, together with Lan Wang, Ph.D., assistant professor of biochemistry and molecular biology at the Miller School, and several members of the labs of Robert G. Roeder, M.D., at The Rockefeller University, Dinshaw J. Patel, Ph.D., at Memorial Sloan-Kettering Cancer Center, and Ari Melnick, M.D., from Weill Cornell Medical College, all in New York. Their findings were published in the online version of the prestigious journal Nature on June 30.

AML is an acute form of leukemia that begins when the stem cells in the bone marrow, which generate new blood cells, fail to develop properly. The cancer cells can then accumulate in the blood and bone marrow, crowding out the normal cells that play critical functions in the body. The survival for adults with AML is poor, with only 10 percent of patients over age 60 surviving five years after diagnosis.

Nimer and Wang, who both joined the Miller School of Medicine recently, have each been studying the AML1-ETO protein — which functions as an oncogene, driving the growth of leukemia cells — for more than a decade. “We are now able to interrupt the progression of ALM1-ETO leukemia, a key finding that will aid in the development of future therapies,” said Wang.

The collaborative study, “A stable transcription factor complex nucleated by oligomeric AML1-ETO controls leukaemogenesis,” focused on the proteins that bind to AML1-ETO or that allow AML1-ETO to expand its repertoire of DNA recognition sequences, and thereby control the transcription of genetic information within cells.

“The ALM1-ETO oncogene likes to travel in packs,” Nimer said, referring to a process called protein oligomerization, where the proteins assemble into a large molecular complex. They can then attract and bind other proteins; together these complexes can function to block the formation of normal blood cells and contribute to the development of new cases of acute leukemia. “Our study shows that preventing the AML1-ETO complex from ‘recruiting’ other proteins halts the progression to leukemia.”

Nimer noted the new study comes nearly 20 years after the AML1-ETO oncogene was first isolated in the laboratory. “The biochemistry is so complex that it has taken decades for researchers around the world to gather the information that could lead to the development of a targeted therapy for this form of leukemia,” he said. A similar “blocking” strategy has been developed to fight lymphoma, although it is not yet widely used in treatment.

Diagnosing AML1-ETO-driven leukemias typically involves chromosome analysis or polymerase chain reaction, Nimer said. “An accurate diagnosis is essential in developing the most effective treatment for each patient’s leukemia. We plan to be in the forefront in order to develop new strategies to prevent the protein interactions that lead to AML1-ETO-driven leukemia.”

Nimer said the study reflects Sylvester’s scientific collaboration with two other leading medical laboratories, and funding for this research was largely provided by the Starr Foundation. The grant was submitted by co-authors Dinshaw J. Patel, Ph.D., chair in experimental therapeutics in the Structural Biology Program at Memorial Sloan-Kettering Cancer Center, Robert G. Roeder, Ph.D., professor of laboratory of biochemistry and molecular biology at The Rockefeller University, and Nimer, professor of medicine, biochemistry and molecular biology. Other co-authors were from those two institutions and from Weill Cornell Medical College, and the Max Planck Institute for Biophysical Chemistry in Germany.

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