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Epigenetic pathway and new drug show promise in reversing a hard-to-treat childhood cancer
Date:7/11/2011

ates for treating other childhood leukemias has reached 80 or 90 percent," Armstrong said. "However, we still only achieve about 50 percent success in treating MLL-rearranged leukemias. We need to find better ways of caring for these patients, and these results give us confidence that we are heading in the right direction."

Armstrong had previously shown that MLL-rearranged leukemia cells have a unique pattern of histone methylation, a specific kind of epigenetic modification, caused by an enzyme called Dot1l. This enzyme, which is recruited to cancer-promoting genes by the MLL-fusion protein, attaches a methyl group to a particular amino acid on a histone (a scaffolding protein that helps manage gene activation) called histone H3.

In the first of the two Cancer Cell papers, Armstrong, along with Kathrin Bernt, MD, and Andrew Kung, MD, PhD, of Children's and Dana-Farber, confirms that genes targeted by a MLL fusion protein called MLL-AF9 are associated with inappropriately methylated histone H3 proteins. By genetically inactivating Dot1l, the team could eliminate the MLL-specific histone methylation and gene expression patterns in cells from a mouse model of the disease. In addition, they found that mice injected with leukemia cells lacking Dot1l did not develop leukemia, in contrast to those injected with leukemia cells possessing active Dot1l.

"Our previous work suggested that Dot1l was the culprit behind the abnormal methylation patterns in MLL-rearranged cells," Armstrong noted. "We now know that these leukemias fully rely on this enzyme and the methylation pattern it generates in order to persist and grow.

"While methylation tags on histones are very difficult to manipulate directly," he added, "Dot1l is much easier to target therapeutically."

The second Cancer Cell paper, co-authored by Armstrong, Bernt, Kung and collaborators at the biotechnology company Epizyme, takes the Dot1l findings a step furth
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Contact: Rob Graham
Rob.Graham@childrens.harvard.edu
617-919-3110
Children's Hospital Boston
Source:Eurekalert

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