An agent that inhibits alterations in DNA structure (epigenetic changes) may help overcome poor outcomes in childhood leukemia caused by MLL gene rearrangements.

The success rates for treating most childhood leukemias have reached 80% to 90%, but only about 50% for MLL-rearranged disease, according to Scott Armstrong, MD, PhD, a pediatric oncologist at Children’s Hospital Boston (Massachusetts) and Dana-Farber Cancer Institute, also in Boston.

Armstrong coauthored two studies appearing in the same issue of Cancer Cell (2011;20[1]:53-65, 66-78). In one report, the researchers established that epigenetic changes wreak genomic havoc with white blood cells in MLL-rearranged leukemia; in the other, the same team, collaborating with a biotechnology company, showed that a new drug could block the changes and deactivate cancer-promoting genes to halt the growth of this disease.

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“We have known for a while that MLL leukemias arise from widespread alterations not in the genetic code itself, but in the structure of the DNA and the proteins associated with it,” explained Armstrong in a separate statement. “We now show that these epigenetic changes indeed turn on cancer-promoting genes within white blood cells and ultimately cause the leukemia.”

But even more important, observed Armstrong, “We show that we can reverse this process.”

The first paper by Armstrong and colleagues describes how inactivating an enzyme called Dot1l helped stop MLL rearrangement in mice. Moreover, leukemia cells lacking this enzyme did not cause leukemia in mice, whereas leukemia cells with active Dot1l did cause the disease to develop

The second paper details how a Dot1l-inhibiting molecule called EPZ004777 eliminates abnormal epigenetic modification patterns in MLL cells. Mice with MLL-rearranged leukemia showed increased survival when treated with EPZ004777. In addition, treatment with this molecule mirrored those achieved by inactivating Dot1l in genetically engineered mice and caused MLL-rearranged leukemia cells to die off in about 2 weeks’ time.