Explore the role of isocitrate dehydrogenase (IDH) mutations in cancer

Normal IDH activity becomes aberrant

IDH enzymes help generate metabolites and provide energy for cells.1-3 A mutation in an IDH enzyme in cancer was first identified in colon cancer in 2006.4 It was subsequently discovered that IDH1 and IDH2 mutations were highly prevalent in glioma.5 IDH1 and IDH2 mutations have since been reported in a multitude of cancers, including acute myeloid leukemia (AML), cholangiocarcinoma, and chondrosarcoma.3

In cancer, IDH mutations lead to aberrant DNA methylation and altered gene expression.6,7 They may promote leukemogenesis in AML and tumorigenesis in glioma and are associated with disease progression.8-12

Normal role of IDH

IDH mutations in cancer

Understanding Mutations in IDH Brochure

References
  1. Reitman ZJ, Yan H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J Natl Cancer Inst. 2010;102(13):932-941.
  2. Yoshihara T, Hanamoto T, Munakata R, Tajiri R, Ohsumi M, Yokota S. Localization of cytosolic NADP-dependent isocitrate dehydrogenase in the peroxisomes of rat liver cells: biochemical and immunocytochemical studies. J Histochem Cytochem. 2001;49(9):1123-1131.
  3. Krell D, Mulholland P, Frampton AE, Krell J, Stebbing J, Bardella C. IDH mutations in tumorigenesis and their potential role as novel therapeutic targets. Future Oncol. 2013;9(12):1923-1935.
  4. Prensner JR, Chinnaiyan AM. Metabolism unhinged: IDH mutations in cancer. Nat Med. 2011;17(3):291-293.
  5. Yan H, Parsons W, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8):765-773.
  6. McKenney AS, Levine RL. Isocitrate dehydrogenase mutations in leukemia. J Clin Invest. 2013;123(9):3672-3677.
  7. Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18(6):553-567.
  8. Welch JS, Ley TJ, Link DC, et al. The origin and evolution of mutations in acute myeloid leukemia. Cell. 2012;150(2):264-278.
  9. Wang F, Travins J, DeLaBarre B, et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science. 2013;340(6132):622-626.
  10. Kernytsky A, Wang F, Hansen E, et al. IDH2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibition. Blood. 2015;125(2):296-303.
  11. Cairns RA, Mak TW. Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities. Cancer Discov. 2013;3(7):730-741.
  12. Turkalp Z, Karamchandani J, Das S. IDH mutation in glioma: new insights and promises for the future. JAMA Neurol. 2014;71(10):1319-1325.
  13. Zdzisińska B, Żurek A, Kandefer-Szerszeń M. Alpha-ketoglutarate as a molecule with pleiotropic activity: well-known and novel possibilities of therapeutic use. Arch Immunol Ther Exp. 2016 Jun 20. [Epub ahead of print].
  14. Su X, Wellen KE, Rabinowitz JD. Metabolic control of methylation and acetylation. Curr Opin Chem Biol. 2016;30:52-60.
  15. Gore AV, Weinstein BM. DNA methylation in hematopoietic development and disease. Exp Hematol. 2016;44(9):783-790.
  16. Tahiliani M, Koh KP, Shen Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324(5929):930-935.
  17. Cardaci S, Ciriolo MR. TCA cycle defects and cancer: when metabolism tunes redox state. Int J Cell Biol. 2012;2012:161837.
  18. Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373(12):1136-1152.

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