A very difficult-to-treat childhood leukemia may benefit from the discovery of a small but potent epigenetic change that launches the cancer but could potentially be reversed relatively easily, preventing cancer-promoting genes from being turned on. Children with the subtype of acute lymphoblastic leukemia (ALL) known as MLL-AF4 have a cure rate of just under 50 percent with chemotherapy, compared with cure rates of ~80 percent for the major types of childhood leukemia.
To figure out why MLL-AF4 is so aggressive, Scott Armstrong and co-workers at Children’s Hospital Boston and the Dana-Farber Cancer Institute developed a mouse model of the disease, which had eluded scientists in the past. Then, the researchers showed that the abnormal fusion protein that characterizes the disease, also known as MLL-AF4, recruits the H3K79 methyltransferase DOT1L to chromatin, which causes aberrant histone H3 methylation.As a result of this epigenetic change, chromosome structure is altered. This jump-starts the activity of a diverse group of genes, including some known to be critical in initiating leukemia.
Studying samples from children with MLL-AF4 leukemias, the team made the same observations. “The fusion protein modifies histones and turns on genes that are not supposed to be turned on, and that initiate the development of the cancer,” says Armstrong. “If you could inhibit that abnormal histone modification, you might be able to reverse the tumorigenic properties of the fusion protein.” A pharmaceutical DOT1L inhibitor hasn’t yet been found, but when the researchers suppressed DOT1L through RNA interference techniques, the abnormally activated genes were turned off. Get all the details at Cancer Cell, November 2008.