动物模型,白血病,异柠檬酸脱氢酶突变 z-bo 2020-11-30 326

　　In recent years, mutations in two metabolic enzymes, isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH1 and IDH2), have been determined to be present in approximately 20% of acute myeloid leukemia (AML) . As a result, the mutant IDH protein has been confirmed as a potential drug target for the treatment of leukemia.

　　Now, a research team at Beth Israel Deaconess Medical Center has created a transgenic mouse model with IDH2 mutations, and in the process, answered a core question, that is, whether these protein IDH mutations are necessary for the initiation and maintenance of leukemia.

　　This study, currently published in Cell Stem Cell, confirms that IDH2 has a powerful carcinogenic effect and supports its use as a therapeutic target for blood cancer. Equally important, this transgenic model provides a tool for evaluating potential mutant IDH2 inhibitors.

　　Author Dr. Pier Paolo Pandolfi explained: The real hope is that one day we can develop drugs to treat patients with IDH2 mutant leukemia. We have demonstrated in transgenic animal models that IDH mutations lead to the initiation of acute leukemia in vivo, and that mutant IDH is necessary for the maintenance of leukemia cells.

　　IDH1 and IDH2 proteins are key enzymes in the TCA cycle. These proteins mutate to acquire a new ability to produce 2-hydroxyglutamate (2HG), which has been shown to accumulate at high levels in cancer patients. The researchers' goal is to create animal models of IDH mutations, inducible and reversible.

　　IDH mutant animal models allow us to solve an important unresolved question: whether the inhibition of IDH mutant proteins during the active stage of the disease has an impact on tumor maintenance or progression. They studied two different models: a retroviral transduction model and a genetic engineering model (in which IDH mice were crossed with mice carrying other leukemia-related gene mutations).

　　In the first model, IDH mutations combined with oncogenes HOXA9 and Meis1a, the results showed that after two weeks, 6 out of 8 animals showed complete remission of symptoms and no leukemia cells were detected. These results, the authors said, are surprising and encouraging, indicating that the occurrence of IDH mutation is an early event, and the occurrence of leukemia transformation is a follow-up event of genetic mutation.

　　Therefore, researchers went on to develop genetically modified models to study the genetics of human leukemia more closely. By crossing IDH2 mutant animals with other leukemia-related gene mutant mice, including the FMS-like tyrosine kinase 3 gene mutation (FLT3), it was found that the mutant IDH2 contributed to the initiation of leukemia in the body.

　　This new study has verified that the IDH mutant protein is a very powerful candidate target for targeted treatment of leukemia.