Second Hits

Two genetic mutations discovered in subset of acute myeloid leukemia

Ann Kathrin EisfeldMutations in two genes that play a role in many solid tumors might help explain why some people develop acute myeloid leukemia (AML), according to a study led by OSUCCC – James researchers.

The CCND1 and CCND2 genes have been implicated in solid tumors, but this recent study provides some of the first data to describe their role in core binding factor acute myeloid leukemia (CBF-AML).

CBF-AML has two subtypes, called t(8;21) and inv(16). Both are caused by chromosomal damage that merges two different genes. But the resulting fusion genes alone are incapable of causing leukemia; a second mutation is necessary.

“The hematology community has long sought to determine what other factors in addition to the fusion genes occur in this special type of leukemia,” says first author Ann-Kathrin Eisfeld, MD, Internal Medicine resident in Ohio State’s Medical Scientist Training Program and a researcher with the OSUCCC – James Leukemia Research Program. Eisfeld works in the laboratories of OSUCCC – James researchers Clara D. Bloomfield, MD, and Albert de la Chapelle, MD, PhD, who led the study.

“We are the first to describe that mutations in CCND1, and among the first to describe that mutations in the sister gene CCND2, are unique features of CBF-AML with t(8;21),” Eisfeld says.

The researchers also found that mutations in CCND2 lead to more aggressive growth of leukemia cell lines. “Based on those results, we are seeking to learn if they actually provide a transformative ‘second hit’ that propels the cells carrying the fusion gene to progress into cancer," Eisfeld adds.

The team analyzed pretreatment bone marrow and peripheral blood samples from 177 adult CBF-AML patients who received similar medical treatment through a national clinical trial conducted at multiple centers across the United States.

The findings could help explain the clinical differences between patients with t(8;21) and those with inv(16), and could also lead to the identification of new potential therapeutic targets.

Published in the journal Leukemia.

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