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A very difficult-to-treat child 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. The study, led by researchers at Children's Hospital Boston and the Dana-Farber Cancer Institute, is the cover article in the November 4 issue of Cancer Cell.
While cure rates for the major types of childhood leukemia are now about 80 percent, they are much lower for patients with a subtype of acute lymphoblastic leukemia (ALL) known as MLL-AF4, which accounts for 5 percent of all ALLs but 70 percent of ALLs striking infants. Children with this form of leukemia suffer rapid relapses and have a cure rate of just under 50 percent with chemotherapy.
"MLL-AF4 leukemias are very difficult to treat and in desperate need of new therapeutic approaches," says senior investigator Scott Armstrong, MD, PhD, of Children's and Dana-Farber. Like other other leukemias, the disease leads to abnormally high numbers of immature, dysfunctional white blood cells that crowd out the bone marrow, interfering with its ability to produce healthy blood cells.
The researchers, led by Armstrong, Andrei Krivtsov, PhD and Zhaohui Feng, also of Children's and Dana-Farber, first developed a mouse model of MLL-AF4, which had eluded scientists in the past. They then showed that the abnormal "fusion" protein that characterizes the disease, also known as MLL-AF4, goes to the cell's DNA and causes abnormal modification of one of the histones, "scaffolding" proteins that give chromosomes their shape and help control gene activation. As a result of this epigenetic change, chromosome structure is altered. This jump-starts activity of a diverse group of genes, including some known to be critical in initiating leukemia.
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