STUDY IDENTIFIES KEY CAUSE OF CHRONIC LEUKEMIA PROGRESSION

OSUCCC-James cancer researchers have discovered a reason why a form of leukemia progresses from its more treatable chronic phase to a life-threatening phase called blast crisis.

The study, led by principal investigator Danilo Perrotti, MD, PhD, of the Molecular Biology and Cancer Genetics Program at the OSUCCC-James, indicates that chronic myeloid leukemia (CML) progresses when immature white blood cells lose a molecule called miR-328. Loss of this molecule traps the cells in a rapidly growing, immature state. The cells soon fill the bone marrow and spill into the bloodstream, a sign that the disease has advanced to the blast-crisis stage.

The research, published in the March 5 issue of the journal Cell, should provide a better understanding of the blast-crisis stage of CML, and it suggests a possible new strategy for treating the disease, the researchers say.

“These findings indicate that the loss of miR-328 is probably essential for progression from the chronic phase of CML to the blast-crisis stage,” Perrotti says. “They also suggest that maintaining the level of this microRNA may represent a new therapeutic strategy for CML blast-crisis patients who do not benefit from targeted agents such as imatinib (Gleevec) and dasatinib (Sprycel).”

The study also revealed a new function for microRNA. Researchers knew that these molecules help regulate the kinds of proteins that cells make, but this study shows for the first time that microRNA molecules can attach directly to protein molecules and alter their function.

In this case, miR-328 binds to a protein that prevents immature blood cells from maturing. “We believe that it normally acts as a decoy molecule, tying up the protein and enabling the white blood cells to mature as they should,” Perrotti says.

During CML progression, however, the level of miR-328 drops, allowing the protein to be extremely active, he says, explaining that this keeps the leukemic white blood cells from maturing and contributes to the transition from the chronic-disease phase to the blast-crisis phase. “These findings may help unravel novel pathways responsible for the initiation and progression of leukemia generally,” says Perrotti, who also is a Scholar of The Leukemia & Lymphoma Society.