[IDH mutations activate Hoxa9/Meis1 and hypoxia pathways in acute myeloid leukemia model mice].
Mutations in isocitrate dehydrogenase (IDH) 1 and 2 are frequently observed in acute myeloid leukemia (AML), glioma, and many other cancers. While wild-type IDHs mediate exchanges between isocitrate and α-ketoglutarate (α-KG), mutant IDHs convert α-KG to oncometabolite 2-hydroxyglutarate (2-HG), which causes dysregulation of a set of α-KG-dependent dioxygenases such as TET, histone demethylase and others. Because mutant IDH has no necessary functions in normal cells, inhibitors directed against mutant IDH are not expected to have the side effects as anti-cancer agents. To determine whether mutant IDH enzymes are valid targets for cancer therapy, we created a mouse model of mutant IDH2-dependent AML. By using a combination of AML model mice with cre-loxp, we conditionally deleted mutant IDH2 from AML mice, which resulted in the loss of leukemia stem cells and significantly delayed the progression of AML. These results indicate that mutant IDHs are promising targets for anticancer therapy.
Division of Hematological Malignancy, National Cancer Center Research Institute.
Yoko
Y
Ogawara
Issay
I
Kitabayashi
D000818:Animals; D004195:Disease Models, Animal; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D015398:Signal Transduction
D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; C097899:homeobox protein HOXA9; D007521:Isocitrate Dehydrogenase