title: Enigmas of IDH mutations in hematology/oncology.
abstract: The discovery of oncogenic mutations in isocitrate dehydrogenase (IDH) enzymes has highlighted the delicate interplay of metabolism, cellular signaling, and transcriptional regulation that was off-focus for some time in the genomic era. Although IDH inhibitors are being evaluated for clinical efficacy, an in-depth understanding of disease pathogenesis linked to IDH mutations is required to develop rational combination treatments and to be evaluated in the clinic. To gain such an understanding, several questions need to be addressed: Why do IDH mutations occur selectively in subsets of a disease entity although they are found to be present in a very heterogeneous set of unrelated tumors? Why are 2-hydroxyglutarate-producing tumors specifically selected for the R-enantiomer and not for the S-enantiomer? Are the changes in 2-hydroxyglutarate-induced DNA methylation primary or secondary alterations in tumorigenesis? What are the roles of hypoxia-inducible factor (HIF) and its prolyl 4-hydroxylases in IDH-mutant tumors? Here, we address these questions and discuss the consequences for basic and clinical research related to IDH-mutant tumors.
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany. Electronic address: heuser.michael@mh-hannover.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Heuser
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Michelle Maria
authors.initials: MM
authors.lastname: Araujo Cruz
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Ramya
authors.initials: R
authors.lastname: Goparaju
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Anuhar
authors.initials: A
authors.lastname: Chaturvedi
mesh_terms: D000818:Animals; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005977:Glutarates / Q000378:metabolism; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D013237:Stereoisomerism
chemical_list: D004791:Enzyme Inhibitors; D005977:Glutarates; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase