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Animal model demonstrates role for metabolic enzyme in acute myeloid leukemia
Date:1/28/2014

that has been shown to accumulate at high levels in cancer patients and is therefore described as an "oncometabolite."

"Our goal was to generate an animal model of mutant IDH that was both inducible and reversible," explains co-lead author Markus Reschke, PhD, an investigator in BIDMC's Cancer Research Institute and Research Fellow in the Pandolfi laboratory. "This enabled us to address an important unanswered question: Does inhibition of mutant IDH proteins in active disease have an effect on tumor maintenance or progression in a living organism?"

Reschke and co-lead author Lev Kats, PhD, also a Research Fellow in the Pandolfi lab, studied two different models: a retroviral transduction model and a genetically engineered model in which IDH mice were crossed to mice harboring other leukemia-relevant mutations.

In the first model, the IDH mutation was combined with the oncogenes HoxA9 and Meis1a, two downstream targets of numerous pathways that are deregulated in AML. The results showed evidence of differentiation within two weeks of genetic deinduction of mutant IDH, and two weeks later, six of eight animals showed complete remission with elimination of any detectable leukemic cells.

These results, say the authors, were both surprising and encouraging, demonstrating a situation in which IDH mutation occurs as an early event and leukemic transformation occurs as a result of subsequent genetic "hits."

"The retroviral model enabled us to observe that mutant IDH2 is essential for the maintenance of HoxA9/Meis1a-induced AML," explains Kats. "But this was still a surrogate model this isn't what happens in human patients, per se."

The investigators, therefore, went on to develop a transgenic model that more closely recapitulates the genetics of human AML.

"By crossing the mutant IDH2 animals with other leukemia-relevant mutations, including mutations in the FMS-like tyrosine kinase 3 [FLT3], we observed t
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Contact: Bonnie Prescott
bprescot@bidmc.harvard.edu
617-667-7306
Beth Israel Deaconess Medical Center
Source:Eurekalert

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