动物造模,白血病 z-bio 2021-04-21 252

　　In recent years, mutations in two metabolic enzymes isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH1 and IDH2) have been found in about 20% of acute myeloid leukemia (AML). As a result, the mutant IDH protein was identified as a potential drug discovery target for the treatment of leukemia.

　　At present, the research team of BethIsraelDeaconessMedicalCenter has created a transgenic mouse model with IDH2 mutations, and in the process answered the following main questions: whether these protein IDH mutations are needed to initiate and maintain leukemia.

　　The latest research published by

　　CellStemCell confirms that IDH2 has a strong carcinogenic effect and supports its use as a therapeutic target for hematological malignancies. 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 will be able to develop a drug to treat patients with IDH2 mutant leukemia. Transgenic animal models show that IDH mutations cause the onset of acute leukemia in vivo, and the mutant IDH is necessary to maintain leukemia cells.

　　IDH1 and IDH2 proteins are important enzymes in the TCA cycle. These proteins are mutated to obtain 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 inducible and reversible IDH mutations.

　　IDH mutant animal models can solve important open problems. Does inhibiting the IDH mutant protein in the active phase of the disease affect the maintenance or progression of the tumor? They studied two different models: a retroviral transduction model and a genetic engineering model (IDH mice were crossed with mice with mutations in other leukemia-related genes). The first model is a combination of IDH mutations and oncogenes HOXA9 and Meis1a, which showed that after 2 weeks, 6 out of 8 animals had complete remission and no leukemia cells were detected. The authors show that these results are surprising and encouraging. The development of IDH mutations is an early event, and the development of leukemia transformation is a follow-up event of gene mutations. Therefore, researchers continue to develop genetically modified models to more closely study the genetics of human leukemia. By mating IDH2 mutants with mice carrying other leukemia-related gene mutations (including FMS-like tyrosine kinase 3 gene mutation (FLT3)), it was found that the mutant IDH2 contributed to the development of leukemia in the body. This new study confirms that the IDH mutant protein is a very strong candidate target for leukemia targeted therapy.