BOSTON In recent years, mutations in two metabolic enzymes, isocitrate dehydrogenase-1 and 2 (IDH1 and IDH2), have been identified in approximately 20 percent of all acute myeloid leukemias (AML). As a result, mutant IDH proteins have been proposed as attractive drug targets for this common form of adult leukemia.
Now a scientific team at Beth Israel Deaconess Medical Center (BIDMC) has generated a transgenic mouse model of the most common IDH2 mutation in human AML, and, in the process, answered a central question of whether these mutant IDH proteins are required for leukemia initiation and maintenance in a living organism.
Currently published on-line in the journal Cell Stem Cell and scheduled to appear in print in March, these new findings confirm a potent oncogenic role for IDH2, and support its relevance as a therapeutic target for the treatment of this widespread blood cancer. Equally important, this transgenic model provides an important new tool for evaluating the pharmacological efficacy of potential mutant IDH2 inhibitors, either alone or in combination with other compounds.
"The real hope is that we would one day be able to treat IDH2-mutant leukemia patients with a drug that targets this genetic abnormality," explains senior author Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Center and the Cancer Research Institute at BIDMC and the George C. Reisman Professor of Medicine at Harvard Medical School. "Our transgenic animal model has now demonstrated that the IDH mutation contributes to the initiation of acute leukemia in vivo and that mutant IDH is essential for the maintenance of leukemic cells even in a genetic setting where mutant IDH is not required for cancer initiation."
IDH1 and IDH2 proteins are critical enzymes in the TCA cycle, which is centrally important to many biochemical pathways. Mutated forms of these proteins gain a novel ability to produce 2-hydroxyglutarate (2HG), a metabolite
|Contact: Bonnie Prescott|
Beth Israel Deaconess Medical Center