Abstract
Molecular and clinical research based on isocitrate dehydrogenase (IDH) mutations is much sought after in glioma research since a decade of its discovery in 2008. IDH enzyme normally catalyzes isocitrate to α-keto-glutarate (α-KG), but once the gene is mutated it produces an ‘oncometabolite’, 2-hydroxyglutarate (2-HG). 2-HG is proposed to inhibit α-KG-dependent dioxygenases and also blocks cellular differentiation. Here, we discuss the role of the IDH1 mutation in gliomagenesis. The review also focuses on the effect of 2-HG on glioma epigenetics, the cellular signaling involved in IDH1 mutant glioma cells and the therapeutic response seen in mutant IDH1(mIDH1) harboring glioma patients in comparison to the patients with wild-type IDH1. The review encompasses the debatable impacts of the mutation on immune microenvironment a propos of various mIDH1 inhibitors in practice or in trials. Recent studies revealing the relation of IDH mutation with the immune microenvironment and inflammatory status in untreated versus treated glioblastoma patients are highlighted with respect to prospective therapeutic targets. Also at the molecular level, the association of mIDH1/2-HG with the intracellular components such as mitochondria and other neighboring cells is discussed.
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The authors would like to acknowledge Dr. Cibin TR for his valuable inputs and suggestions towards the final drafting of the manuscript. BB would like to thank Department of Science and Technology, India for providing the Inspire Fellowship (IF150784). ACR acknowledges Council of Scientific and Industrial Research (09/523(0082)/2014-EMR-1) Government of India for Research Fellowship.
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BB and ACR were the major contributors (designing, searching and writing of the manuscript). MUK, DAN, RP and SG discussed ideas, helped in the outline of the review, and corrected the text. HVE, KK and SG made critical revision for important intellectual content and final approval of the review. The conception of the review was done by SG.
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Bhavya, B., Anand, C.R., Madhusoodanan, U.K. et al. To be Wild or Mutant: Role of Isocitrate Dehydrogenase 1 (IDH1) and 2-Hydroxy Glutarate (2-HG) in Gliomagenesis and Treatment Outcome in Glioma. Cell Mol Neurobiol 40, 53–63 (2020). https://doi.org/10.1007/s10571-019-00730-3
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DOI: https://doi.org/10.1007/s10571-019-00730-3