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→Gene Overview
==Gene Overview==
==Gene Overview==
===Structure and Function===
''IDH1'' and ''IDH2'' encode the two NADP(+)-dependent isocitrate dehydrogenases in humans. IDH1 and IDH2 share approximately 70% sequence homology. There are five ''IDH'' genes in total in the human genome encoding three distinct IDH enzymes: ''IDH1'', ''IDH2'', and ''IDH3'', an NAD(+)-dependent isocitrate dehydrogenase unrelated to ''IDH1'' or ''IDH2''. While IDH2 protein is found in the mitochondria, IDH1 is localised to the cytoplasm and in peroxisomes.
''IDH1'' and ''IDH2'' encode the two NADP(+)-dependent isocitrate dehydrogenases in humans. IDH1 and IDH2 share approximately 70% sequence homology. There are five ''IDH'' genes in total in the human genome encoding three distinct IDH enzymes: ''IDH1'', ''IDH2'', and ''IDH3'', an NAD(+)-dependent isocitrate dehydrogenase unrelated to ''IDH1'' or ''IDH2''. While IDH2 protein is found in the mitochondria, IDH1 is localised to the cytoplasm and in peroxisomes.
IDH1 appears to have a role in glucose sensing through a novel anaplerotic pyruvate cycle where glucose-derived pyruvate enters the TCA cycle through pyruvate carboxylase, is converted to isocitrate, and exits the mitochondria via the citrate-isocitrate carrier[16]. IDH1 converts isocitrate to αKG, producing NADPH, and αKG and/or NADPH promote insulin secretion possibly through modulation of αKG hydroxylases or voltage-gated potassium channels, respectively. Functional studies in mice and mammalian pancreatic islets appear to support this hypothesis[17,18].
IDH1 appears to have a role in glucose sensing through a novel anaplerotic pyruvate cycle where glucose-derived pyruvate enters the TCA cycle through pyruvate carboxylase, is converted to isocitrate, and exits the mitochondria via the citrate-isocitrate carrier[16]. IDH1 converts isocitrate to αKG, producing NADPH, and αKG and/or NADPH promote insulin secretion possibly through modulation of αKG hydroxylases or voltage-gated potassium channels, respectively. Functional studies in mice and mammalian pancreatic islets appear to support this hypothesis[17,18].
===Role in Cancer===
IDH1 mutations are most common in certain glioma subtypes, having been identified in approximately 80% of WHO grade II and III astrocytomas and oligodendrogliomas, and secondary glioblastomas[20]. In the context of glioma, ''IDH1'' mutations are associated with an improved outcome and a younger age at diagnosis[21,22]. They are, however, rare in patients younger than 18 years.
IDH1 mutations are most common in certain glioma subtypes, having been identified in approximately 80% of WHO grade II and III astrocytomas and oligodendrogliomas, and secondary glioblastomas[20]. In the context of glioma, ''IDH1'' mutations are associated with an improved outcome and a younger age at diagnosis[21,22]. They are, however, rare in patients younger than 18 years.
NADPH is required to recharge, activate, or generate reduced glutathione (GSH), thioredoxin, catalase tetramers, and cytochrome p450, which are all involved in cellular protection against oxidative stress. NADPH production in IDH1 R132-mutants is hampered and, moreover, the conversion of αKG to 2HG by these mutants is NADPH-dependent which reduces NADPH levels even further[6]. NADPH has shown to be depleted in colorectal cancer and glioma cells[54,55], although glucose-6-phosphate dehydrogenase (G6PDH) is the major source of NADPH in myeloid cells[56]. 2HG accumulation can also induce oxidative stress independently of ''IDH1'' mutations[57].
NADPH is required to recharge, activate, or generate reduced glutathione (GSH), thioredoxin, catalase tetramers, and cytochrome p450, which are all involved in cellular protection against oxidative stress. NADPH production in IDH1 R132-mutants is hampered and, moreover, the conversion of αKG to 2HG by these mutants is NADPH-dependent which reduces NADPH levels even further[6]. NADPH has shown to be depleted in colorectal cancer and glioma cells[54,55], although glucose-6-phosphate dehydrogenase (G6PDH) is the major source of NADPH in myeloid cells[56]. 2HG accumulation can also induce oxidative stress independently of ''IDH1'' mutations[57].
===Concurrent Mutations===
''IDH1'' mutations do not increase in frequency as gliomas progress, which, coupled with the evidence that ''IDH1'' mutations occur before other genetic changes, suggests that ''IDH1'' mutations are involved early in the transition of a normal cell to a tumour cell[19,58].
''IDH1'' mutations do not increase in frequency as gliomas progress, which, coupled with the evidence that ''IDH1'' mutations occur before other genetic changes, suggests that ''IDH1'' mutations are involved early in the transition of a normal cell to a tumour cell[19,58].
In AML, ''IDH1'' mutations are associated with ''NPM1'' mutations but show negative association with ''CEBPA'' and ''WT1'' mutations[62]. Patients with ''IDH1'' mutations also have a lower frequency of FLT3-ITD mutations and are generally associated with a molecular low-risk group (''NPM1''-mutated and FLT3-ITD-negative)63 and normal cytogenetics[64].
In AML, ''IDH1'' mutations are associated with ''NPM1'' mutations but show negative association with ''CEBPA'' and ''WT1'' mutations[62]. Patients with ''IDH1'' mutations also have a lower frequency of FLT3-ITD mutations and are generally associated with a molecular low-risk group (''NPM1''-mutated and FLT3-ITD-negative)63 and normal cytogenetics[64].
===Therapeutic Implications===
Due to their reliance on oxidative phosphorylation ''IDH1''-mutated cancer cells are vulnerable to inhibitors of this metabolic process. The biguanides metformin and phenformin inhibit NADH dehydrogenase (complex I of the electron transport chain (ETC)), and ''IDH1'' mutations confer sensitivity to these agents[65]; metformin is currently undergoing clinical trial for use in patients with ''IDH1/2''-mutant solid tumours[66].
Due to their reliance on oxidative phosphorylation ''IDH1''-mutated cancer cells are vulnerable to inhibitors of this metabolic process. The biguanides metformin and phenformin inhibit NADH dehydrogenase (complex I of the electron transport chain (ETC)), and ''IDH1'' mutations confer sensitivity to these agents[65]; metformin is currently undergoing clinical trial for use in patients with ''IDH1/2''-mutant solid tumours[66].