title: The driver and passenger effects of isocitrate dehydrogenase 1 and 2 mutations in oncogenesis and survival prolongation.
abstract: Mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key events in the development of glioma, acute myeloid leukemia (AML), chondrosarcoma, intrahepatic cholangiocarcinoma (ICC), and angioimmunoblastic T-cell lymphoma. They also cause D-2-hydroxyglutaric aciduria and Ollier and Maffucci syndromes. IDH1/2 mutations are associated with prolonged survival in glioma and in ICC, but not in AML. The reason for this is unknown. In their wild-type forms, IDH1 and IDH2 convert isocitrate and NADP(+) to α-ketoglutarate (αKG) and NADPH. Missense mutations in the active sites of these enzymes induce a neo-enzymatic reaction wherein NADPH reduces αKG to D-2-hydroxyglutarate (D-2HG). The resulting D-2HG accumulation leads to hypoxia-inducible factor 1α degradation, and changes in epigenetics and extracellular matrix homeostasis. Such mutations also imply less NADPH production capacity. Each of these effects could play a role in cancer formation. Here, we provide an overview of the literature and discuss which downstream molecular effects are likely to be the drivers of the oncogenic and survival-prolonging properties of IDH1/2 mutations. We discuss interactions between mutant IDH1/2 inhibitors and conventional therapies. Understanding of the biochemical consequences of IDH1/2 mutations in oncogenesis and survival prolongation will yield valuable information for rational therapy design: it will tell us which oncogenic processes should be blocked and which "survivalogenic" effects should be retained.
authors.affiliation: Department of Cell Biology & Histology, Academic Medical Center, University of Amsterdam, The Netherlands. Electronic address: r.j.molenaar@amc.uva.nl.
authors.forename: Remco J
authors.initials: RJ
authors.lastname: Molenaar
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Radivoyevitch
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
authors.affiliation: Department of Cell Biology & Histology, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: Cornelis J F
authors.initials: CJ
authors.lastname: van Noorden
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: Fonnet E
authors.initials: FE
authors.lastname: Bleeker
mesh_terms: D063646:Carcinogenesis; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000502:physiology; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology / Q000401:mortality* / Q000628:therapy; D018384:Oxidative Stress
chemical_list: C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: Acute myeloid leukemia; D-2-hydroxyglutarate; Glioma; IDH1; IDH2; NADPH