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12.17.2013

Sylvester Study Finds Potential New Approach to Treating Leukemia

A Miller School research study has found a potential new approach to halting the growth of acute myelogenous leukemia (AML), a deadly blood-borne cancer in adults and children.

“We found that blocking an enzyme called PRMT4 caused leukemia cells to die,” said Stephen D. Nimer, M.D., Director of the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine. “This study indicates that targeting PRMT4 holds potential as a novel therapy for AML.”

Nimer’s study, “PRMT4 blocks myeloid differentiation by assembling a methyl-RUNX1-dependent repressor complex,” was published December 12 in the journal Cell Reports. It is the latest in a series of studies led by Nimer probing the genetic and cellular processes that lead to AML, and reflects a series of collaborations established among scientists at UM, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, University of Alabama, Birmingham, and other institutions.

About 14,000 new cases of AML are diagnosed each year in the United States, and the five-year survival rate for patients is less than 30 percent. AML is an acute form of leukemia that begins when blood cells formed in the bone marrow fail to develop properly. Instead of maturing into normal cells, the leukemia cells remain at an immature stage, which prolongs their existence, and allows them to spread throughout the body.

“For decades, my laboratory team has been trying to find enzymes that affect the leukemia process,” said Nimer. “We have learned a great deal about the genetic and cellular processes that lead to AML, but we have not been able to find a way to inhibit their function until recently.”

PRMT4 is a member of the protein arginine methyltransferase (PRMT) family of enzymes that “turn genes on or off” at the cellular level. Nimer and his lab group have been at the forefront of efforts to decipher the role of the PRMT enzymes in the normal development of stem cells from the bone marrow into mature blood cells, a process called hematopoiesis.

PRMT4 plays an important role in a number of biological processes, including muscle cell differentiation and the development of T-cells that play a key role in the body’s immune system. But prior to Nimer’s study, PRMT4’s role in leukemia was unknown.

“We found a high level of PRMT4 in AML patient samples and identified the mechanism by which this blocked the differentiation of human stem/progenitor cells,” Nimer said. “By repressing the normal development mechanism, these cells simply remained in an immature stage. But depleting PRMT4 caused the leukemia cells to die.”

Noting that major U.S. drug companies are now working on epigenetic enzyme inhibitors for cancer and other medical conditions, Nimer said, “It is our hope that we will be able to use this approach against leukemia cells, and that our work will accelerate clinical research into new treatments for this form of cancer.”

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