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Cure rates for most childhood leukemias are now about 80 percent, but they are much lower for children with a subtype of acute lymphoblastic leukemia (ALL), in which a gene called MLL is mutated. Now, a study led by Children’s Hospital Boston’s Scott Armstrong, MD, PhD, Andrei Krivtsov, PhD, and Zhaohui Feng, of Hematology/Oncology, suggests a relatively easy way to prevent cancer-causing genes from turning on in this form of ALL, which accounts for 70 percent of ALLs in infants.
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DNA packaging provides a target for leukemia Giving chromosomes their structure and shape, strands of DNA, shown in gray, are coiled around histones, depicted as spheres. In MLL-rearranged acute lymphoblastic leukemia (ALL), a form of acute lymphoblastic leukemia affecting infants, an enzyme call DOT1L modifies the histones in an abnormal way (as indicated in orange) that activates cancer-promoting genes. Drugs inhibiting DOT1L could prevent a variety of cancerous changes in cells. |
In the November 4 Cancer Cell, they show that the abnormal protein that characterizes the disease, called MLL-AF4, goes to a white blood cell’s DNA and alters one of the histones, the "scaffolding"proteins that DNA strands wrap around. The change alters the structure of the chromosome, triggering a diverse group of genes that normally aren’t turned on, including some that are critical in initiating leukemia.
While MLL-AF4 itself would be difficult to target chemically, it turns out that it acts via an enzyme called DOT1L, a much easier target. It therefore might be possible to silence a variety of genes that contribute to malignancy in a single chemical maneuver. Dr. Armstrong’s lab is now searching for small-molecule drugs that inhibit DOT1L. "Reversal of histone modifications could be an important therapeutic approachfor MLL-AF4 and potentially for other cancers,"he says.
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