4,169
edits
Changes
→Therapeutic Implications
==Cancer Category/Type==
==Cancer Category/Type==
Glioma, astrocytoma, oligodendroglioma, acute myeloid leukaemia, myelodysplastic syndrome, lymphoma, prostate cancer, thyroid cancer
* Glioma
Put your text here
* Astrocytoma
Put your text here
* Oligodendroglioma
Put your text here
* Acute myeloid leukaemia
Put your text here
* Myelodysplastic syndrome
Put your text here
* Lymphoma
Put your text here
* Prostate cancer
Put your text here
* Thyroid cancer
Put your text here
==Gene Overview==
==Gene Overview==
NADP+-dependent isocitrate dehydrogenases function as homodimers to catalyse the reversible NAPD+-dependent oxidative decarboxylation of isocitrate to produce alpha-ketoglutarate (αKG), a key molecule in the tricarboxylic acid (TCA) cycle. In the process, NADP+ is reduced into NADPH which is required for cellular detoxification processes.
NADP+-dependent isocitrate dehydrogenases function as homodimers to catalyse the reversible NAPD+-dependent oxidative decarboxylation of isocitrate to produce alpha-ketoglutarate (αKG), a key molecule in the tricarboxylic acid (TCA) cycle. In the process, NADP+ is reduced into NADPH which is required for cellular detoxification processes.
IDH1 is most highly expressed in the mammalian liver, with moderate expression in other tissues[1]. A C-terminal peroxisome targeting signal 1 sequence allows for its peroxisomal localisation[2]. The IDH1 protein is comprised of a large domain (residues 1-103 and 286-414, NM_005896.2/NP_005887.2), a small domain (residues 104-136 and 186-285, NM_005896.2/NP_005887.2) and a clasp domain (residues 137-185, NM_005896.2/NP_005887.2)[3]. The clasp domain holds together two IDH1 subunits and the enzyme active site is formed in a cleft created by the large and small domains of each subunit. Each active site can bind NADP+ and a metal ion in addition to the isocitrate substrate.
''IDH1'' is most highly expressed in the mammalian liver, with moderate expression in other tissues [1]. A C-terminal peroxisome targeting signal 1 sequence allows for its peroxisomal localization [2]. The IDH1 protein is comprised of a large domain (residues 1-103 and 286-414, NM_005896.2/NP_005887.2), a small domain (residues 104-136 and 186-285, NM_005896.2/NP_005887.2) and a clasp domain (residues 137-185, NM_005896.2/NP_005887.2) [3]. The clasp domain holds together two IDH1 subunits and the enzyme active site is formed in a cleft created by the large and small domains of each subunit. Each active site can bind NADP+ and a metal ion in addition to the isocitrate substrate.
With no bound substrate, the Asp279 residue (NM_005896.2/NP_005887.2) occupies the active site where isocitrate would ordinarily form a hydrogen bond with the Ser94 residue (NM_005896.2/NP_005887.2). This steric hindrance prohibits substrate binding until Asp279 (NM_005896.2/NP_005887.2) moves away, contacting Arg132 (NM_005896.2/NP_005887.2) in the process[3]. Once the isocitrate substrate is bound, it forms three hydrogen bonds with Arg132 (NM_005896.2/NP_005887.2)[4]. Arg132 (NM_005896.2/NP_005887.2) therefore plays a critical role in the conformational changes of the IDH enzyme that allow the enzyme to function normally.
With no bound substrate, the Asp279 residue (NM_005896.2/NP_005887.2) occupies the active site where isocitrate would ordinarily form a hydrogen bond with the Ser94 residue (NM_005896.2/NP_005887.2). This steric hindrance prohibits substrate binding until Asp279 (NM_005896.2/NP_005887.2) moves away, contacting Arg132 (NM_005896.2/NP_005887.2) in the process [3]. Once the isocitrate substrate is bound, it forms three hydrogen bonds with Arg132 (NM_005896.2/NP_005887.2) [4]. Arg132 (NM_005896.2/NP_005887.2) therefore plays a critical role in the conformational changes of the IDH enzyme that allow the enzyme to function normally.
The conversion of isocitrate to αKG for use in the TCA cycle is primarily carried out by IDH3 in mitochondria. Although the expression profile of genes involved in metabolism is altered in IDH1-mutated cells[5], IDH1 likely evolved primarily for the purpose of NADPH production and is the main producer of NADPH in the brain[6]. NADPH generated by IDH1 contributes to the cellular defence against reactive oxygen species (ROS), and IDH1 activity increases in response to oxidative insults[7,8]. IDH1 can also modulate the availability of αKG, which itself can function as a potent antioxidant[8].
The conversion of isocitrate to αKG for use in the TCA cycle is primarily carried out by IDH3 in mitochondria. Although the expression profile of genes involved in metabolism is altered in IDH1-mutated cells [5], IDH1 likely evolved primarily for the purpose of NADPH production and is the main producer of NADPH in the brain[6]. NADPH generated by IDH1 contributes to the cellular defence against reactive oxygen species (ROS), and IDH1 activity increases in response to oxidative insults [7,8]. IDH1 can also modulate the availability of αKG, which itself can function as a potent antioxidant [8].
IDH1 deficiency leads to increased lipid peroxidation, oxidative DNA damage, intracellular peroxide generation, and decreased survival after oxidant exposure, while overexpression confers protection from these effects[9]. Cellular IDH1 levels are associated with decreased apoptosis after exposure to ultraviolet B radiation and gamma radiation[10–12]. Despite playing such a crucial role in oxidative stress response, IDH1 is itself inactivated by oxidation[13]. Other antioxidant enzymes may protect against this inactivation, and cells may respond with increased IDH1 synthesis[14].
IDH1 deficiency leads to increased lipid peroxidation, oxidative DNA damage, intracellular peroxide generation, and decreased survival after oxidant exposure, while overexpression confers protection from these effects [9]. Cellular IDH1 levels are associated with decreased apoptosis after exposure to ultraviolet B radiation and gamma radiation [10–12]. Despite playing such a crucial role in oxidative stress response, IDH1 is itself inactivated by oxidation [13]. Other antioxidant enzymes may protect against this inactivation, and cells may respond with increased IDH1 synthesis [14].
NADPH provided by IDH1 is also used in hepatocytes for peroxisomal fat and cholesterol synthesis; in this context, IDH1 expression is regulated by sterol regulatory element-binding proteins 1a and 2[15].
NADPH provided by IDH1 is also used in hepatocytes for peroxisomal fat and cholesterol synthesis; in this context, IDH1 expression is regulated by sterol regulatory element-binding proteins 1a and 2 [15].
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===
===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.
Up to 40% of chondrosarcomas have been observed with IDH1 mutations, where they predict a shorter survival than in patients without ''IDH1'' mutations. There are no clear associations with ''IDH1'' mutation status and histological grade or age at diagnosis in the context of chondrosarcomas[23,24]. ''IDH1'' mutations are not observed in other mesenchymal tumours. One study found somatic ''IDH1'' mutations in a majority (~80%) of enchondromas and spindle cell hemangiomas from patients with Ollier disease and Maffucci syndrome[25].
Up to 40% of chondrosarcomas have been observed with ''IDH1'' mutations, where they predict a shorter survival than in patients without ''IDH1'' mutations. There are no clear associations with ''IDH1'' mutation status and histological grade or age at diagnosis in the context of chondrosarcomas [23,24]. ''IDH1'' mutations are not observed in other mesenchymal tumours. Somatic ''IDH1'' mutations were reported in a majority (~80%) of enchondromas and spindle cell hemangiomas from patients with Ollier disease and Maffucci syndrome [25].
Although ''IDH1'' mutations are rare in gastrointestinal malignancies, they are found in around 20% of intrahepatic cholangiocarcinomas (ICC). In this context, IDH1 mutations are associated with a longer time to tumour recurrence and a lower probability of recurrence[26–28]. The prognostic outlook for overall survival in these patients is unclear as data in the literature is mixed[26,29,30].
Although ''IDH1'' mutations are rare in gastrointestinal malignancies, they are found in around 20% of intrahepatic cholangiocarcinomas (ICC). In this context, ''IDH1'' mutations are associated with a longer time to tumor recurrence and a lower probability of recurrence [26–28]. The prognostic outlook for overall survival in these patients is unclear as data in the literature is mixed [26,29,30].
Approximately 8% of acute myeloid leukaemias (AML) harbour ''IDH1'' mutations, although the frequency is higher in patients with normal karyotype[31]. Studies have been conflicted regarding the prognostic outlook of ''IDH1'' mutations in AML, but a meta-analysis of published data in 2017 found that overall survival and event-free survival were negatively impacted by IDH1 mutations, particularly in patients with normal karyotype[32]. The cumulative incidence of relapse in patients with intermediate-risk karyotype was improved, however. Interestingly, the synonymous single nucleotide polymorphism rs11554137 in ''IDH1'' was also associated with poorer overall survival. ''IDH1''-mutated AML is not found significantly more frequently in younger patients[31]. ''IDH1'' mutations are seen more often in the M1 French-American-British AML subtype when compared to ''IDH1'' wild-type AML[33].
Approximately 8% of acute myeloid leukemias (AML) harbor ''IDH1'' mutations, although the frequency is higher in patients with normal karyotype [31]. Studies have been conflicted regarding the prognostic outlook of ''IDH1'' mutations in AML, but a meta-analysis of published data in 2017 found that overall survival and event-free survival were negatively impacted by ''IDH1'' mutations, particularly in patients with normal karyotype [32]. In contrast, the cumulative incidence of relapse in patients with intermediate-risk karyotype was improved. Interestingly, the synonymous single nucleotide polymorphism rs11554137 in ''IDH1'' was also associated with poorer overall survival. ''IDH1''-mutated AML is not found significantly more frequently in younger patients [31]. ''IDH1'' mutations are seen more often in the M1 French-American-British AML subtype when compared to ''IDH1'' wild-type AML [33].
''IDH1'' mutations are seen less commonly in other haematological malignancies such as myelodysplastic syndrome[34] and also in cancers of the prostate and thyroid[19], and are less well-studied in these contexts. Mutations of ''IDH1'' have been shown to often be stem or early subclonal events in carcinogenesis in all cancers studied thus far, including AML[25,35–38].
''IDH1'' mutations are seen less commonly in other hematological malignancies such as myelodysplastic syndrome [34] and also in cancers of the prostate and thyroid [19], and are less well-studied in these contexts. Mutations of ''IDH1'' have been shown to often be stem or early subclonal events in carcinogenesis in all cancers studied thus far, including AML [25,35–38].
The precise mechanisms linking ''IDH1'' mutations to various cancers are as yet unknown and are likely to be tissue-specific, but ''IDH1''-mutant cells do exhibit defects in multiple cellular processes. The most commonly seen IDH1 variants across all tumour types are heterozygous missense mutations at Arg132 (R132, NM_005896.2/NP_005887.2)[19]. Consistent with the role of R132 in active site conformation transition, alteration of R132 changes the equilibrium between open and closed conformations[39]. The IDH1 R132 mutation results in decreased enzyme affinity for isocitrate[4] and reduced NADPH production[20]. Most notably, the mutation also leads to IDH1 gaining the ability to reduce αKG to D-2-hydroxyglutarate (2HG)[39]. This neomorphic activity causes accumulation of 2HG and reduction of αKG levels.
The precise mechanisms linking ''IDH1'' mutations to various cancers are as yet unknown and are likely to be tissue-specific, but ''IDH1''-mutant cells do exhibit defects in multiple cellular processes. The most commonly seen ''IDH1'' variants across all tumor types are heterozygous missense mutations at Arg132 (R132, NM_005896.2/NP_005887.2) [19]. Consistent with the role of R132 in active site conformation transition, alteration of R132 changes the equilibrium between open and closed conformations [39]. The ''IDH1'' R132 mutation results in decreased enzyme affinity for isocitrate [4] and reduced NADPH production [20]. Most notably, the mutation also leads to IDH1 gaining the ability to reduce αKG to D-2-hydroxyglutarate (2HG) [39]. This neomorphic activity causes accumulation of 2HG and reduction of αKG levels.
Due to this altered enzyme function, IDH1 R132 mutants exhibit complex metabolic perturbations. Like other Warburg-like cancer cells, IDH1 wild-type glioma overexpresses enzymes involved in anaerobic glycolysis[5], as glycolysis and lactate production has the ability to generate both the energy and carbon required for sustained proliferation[41]. IDH1 R132 mutant glioma in contrast downregulates glycolytic enzymes, instead preferring to catabolise glutamate and glucose in the TCA cycle to produce αKG[5]. Genes downstream of isocitrate in the TCA cycle are downregulated in IDH1 R132 mutant glioma while expression of genes functioning upstream of isocitrate is increased[5]. IDH1 R132 mutant cells are therefore more reliant on oxidative phosphorylation compared to IDH1 wild-type cells. The metabolic rewiring in IDH1 R132 mutants is further evidenced by observations of increased mitochondrial gene expression and mitochondrial number in mutant ICC cells[36].
Due to this altered enzyme function, ''IDH1'' R132 mutants exhibit complex metabolic perturbations. Like other Warburg-like cancer cells, ''IDH1'' wild-type glioma overexpresses enzymes involved in anaerobic glycolysis [5], as glycolysis and lactate production has the ability to generate both the energy and carbon required for sustained proliferation [41]. ''IDH1'' R132 mutant glioma in contrast downregulates glycolytic enzymes, instead preferring to catabolise glutamate and glucose in the TCA cycle to produce αKG [5]. Genes downstream of isocitrate in the TCA cycle are downregulated in ''IDH1'' R132 mutant glioma while expression of genes functioning upstream of isocitrate is increased [5]. ''IDH1'' R132 mutant cells are therefore more reliant on oxidative phosphorylation compared to ''IDH1'' wild-type cells. The metabolic rewiring in ''IDH1'' R132 mutants is further evidenced by observations of increased mitochondrial gene expression and mitochondrial number in mutant ICC cells [36].
Much of the work exploring the role of IDH1 in cancer has revolved around the suggestion that 2HG functions as an ‘onco-metabolite’. 2HG accumulation and the concomitant depletion of αKG has been implicated in the stabilisation of hypoxia-inducible factor 1α (HIF-1α), a transcription factor which modulates apoptosis, cell survival, and angiogenesis and is involved in tumourigenesis[4]. This is through inhibition of the αKG-dependent HIF hydroxylases, negative regulators of HIF-1α, either through competitive binding of 2HG over αKG or by the depletion of αKG[42]. In AML cells 2HG has been shown to inhibit the activity of mitochondrial cytochrome c oxidase, which besides impacting oxidative metabolism also puts IDH1 R132 mutant cells on the brink of BAX/BAK-mediated apoptosis[43], and evidence suggests the case is similar in glioma[44]. The NAD+ salvage pathway enzyme nicotinate phosphoribosyltransferase (NAPRT1) is also inhibited by 2HG in glioma cells[45].
Much of the work exploring the role of ''IDH1'' in cancer has revolved around the suggestion that 2HG functions as an ‘onco-metabolite’. 2HG accumulation and the concomitant depletion of αKG has been implicated in the stabilization of hypoxia-inducible factor 1α (''HIF-1α''), a transcription factor which modulates apoptosis, cell survival, and angiogenesis and is involved in tumorigenesis [4]. This is through inhibition of the αKG-dependent HIF hydroxylases, negative regulators of HIF-1α, either through competitive binding of 2HG over αKG or by the depletion of αKG [42]. In AML cells 2HG has been shown to inhibit the activity of mitochondrial cytochrome c oxidase, which besides impacting oxidative metabolism also puts ''IDH1'' R132 mutant cells on the brink of BAX/BAK-mediated apoptosis [43], and evidence suggests the case is similar in glioma [44]. The NAD+ salvage pathway enzyme nicotinate phosphoribosyltransferase (''NAPRT1'') is also inhibited by 2HG in glioma cells [45].
2HG production impacts DNA repair by inhibiting the αKG-dependent DNA repair enzyme alkB homolog[46] and DNA damage response proteins lysine-specific methylase 4A and B (KDM4A/B)[47]. The altered histone methylation due to KDM4A/B inhibition results in downregulation of the DNA repair protein ATM[48]. This is consistent with the observation that IDH1 R132 mutant cells have increased DNA damage[47,48], although the DNA repair defects only seem to extend to the homologous recombination pathway and not the non-homologous end-joining pathway[47].
2HG production impacts DNA repair by inhibiting the αKG-dependent DNA repair enzyme alkB homolog [46] and DNA damage response proteins lysine-specific methylase 4A and B (''KDM4A/B'') [47]. The altered histone methylation due to KDM4A/B inhibition results in downregulation of the DNA repair protein ATM [48]. This is consistent with the observation that ''IDH1'' R132 mutant cells have increased DNA damage [47,48], although the DNA repair defects only seem to extend to the homologous recombination pathway and not the non-homologous end-joining pathway [47].
Increasingly, αKG and 2HG have been implicated in epigenetic regulation of gene expression, and widespread hypermethylation has been reported in IDH1 R132 mutant glioma and leukemia[49,50]. This phenotype has been referred to as the CpG island methylator phenotype (CIMP)[51]. 2HG has been established as an inhibitor of αKG-dependent deoxygenases involved in histone demethylation, including lysine-specific methylases as mentioned above as well as the myeloid tumour suppressor TET2[52]. Downstream effects include the downregulation of ''ATM'', as already described, and likely also the expression of branched-chain amino acid transaminase 1 (''BCAT1''), which metabolises branched chain amino acids as a nitrogen source for neurotransmitter glutamate synthesis[53].
Increasingly, αKG and 2HG have been implicated in epigenetic regulation of gene expression, and widespread hypermethylation has been reported in ''IDH1'' R132 mutant glioma and leukemia [49,50]. This phenotype has been referred to as the CpG island methylator phenotype (CIMP) [51]. 2HG has been established as an inhibitor of αKG-dependent deoxygenases involved in histone demethylation, including lysine-specific methylases as mentioned above as well as the myeloid tumor suppressor ''TET2'' [52]. Downstream effects include the downregulation of ''ATM'', as already described, and likely also the expression of branched-chain amino acid transaminase 1 (''BCAT1''), which metabolizes branched chain amino acids as a nitrogen source for neurotransmitter glutamate synthesis [53].
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===
===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].
''TP53'' mutations have been associated with ''IDH1''-mutated astrocytoma and glioblastoma more than with other glioma subtypes[20,59], and astrocytomas are thought to develop via ''TP53'' and ''ATRX'' mutations subsequent to ''IDH1'' mutations. Astrocytomas associated with germline ''TP53'' mutations were found to have somatic ''IDH1'' Arg123Cys (NM_005896.2/NP_005887.2) mutations which are otherwise rare in this malignancy, suggesting the preferential occurrence of this specific mutation in cells that already contain a ''TP53'' mutation[60].
''TP53'' mutations have been associated with ''IDH1''-mutated astrocytoma and glioblastoma more than with other glioma subtypes [20,59], and astrocytomas are thought to develop via ''TP53'' and ''ATRX'' mutations subsequent to ''IDH1'' mutations. Astrocytomas associated with germline ''TP53'' mutations were found to have somatic ''IDH1'' Arg123Cys (NM_005896.2/NP_005887.2) mutations which are otherwise rare in this malignancy, suggesting the preferential occurrence of this specific mutation in cells that already contain a ''TP53'' mutation [60].
Loss of chromosome arms 1p and 19q is observed more frequently in oligodendroglial tumours with ''IDH1'' mutations compared to other ''IDH1''-mutated or ''IDH1'' wild-type gliomas[20]. Oligodendrogliomas often develop mutations in the ''TERT'' promoter in addition to 1p/19q deletions after ''IDH1'' mutation[61], and these are thought to be important events in their developmental pathway.
Loss of chromosome arms 1p and 19q is observed more frequently in oligodendroglial tumours with ''IDH1'' mutations compared to other ''IDH1''-mutated or ''IDH1'' wild-type gliomas [20]. Oligodendrogliomas often develop mutations in the ''TERT'' promoter in addition to 1p/19q deletions after ''IDH1'' mutation [61], and these are thought to be important events in their developmental pathway.
Other genetic changes common to glioma such as epidermal growth factor receptor (''EGFR'') amplification, cyclin-dependent kinase inhibitor 2A or 2B (''CDKN2A/2B'') deletion, and phosphatase or tensin homolog (''PTEN'') mutations occur less frequently in IDH1-mutated malignancies compared to those with wild-type IDH1[20].
Other genetic changes common to glioma such as epidermal growth factor receptor (''EGFR'') amplification, cyclin-dependent kinase inhibitor 2A or 2B (''CDKN2A/2B'') deletion, and phosphatase or tensin homolog (''PTEN'') mutations occur less frequently in ''IDH1''-mutated malignancies compared to those with wild-type ''IDH1'' [20].
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===
===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 tumors [66].
''IDH1''-mutated cells also have a dependence on the glutaminolysis pathway. Although ''IDH1''-mutated cells need αKG to produce 2HG, they also restrict αKG production[5]. Producing αKG from glutamine allows for an alternative source of αKG in ''IDH''-mutated cells, but makes the cells vulnerable to inhibition of glutaminolysis with agents such as aminooxyacetic acid, BPTES, zaprinast, and chloroquinine in various cell types[67–70].
''IDH1''-mutated cells also have a dependence on the glutaminolysis pathway. Although ''IDH1''-mutated cells need αKG to produce 2HG, they also restrict αKG production [5]. Producing αKG from glutamine allows for an alternative source of αKG in ''IDH''-mutated cells, but makes the cells vulnerable to inhibition of glutaminolysis with agents such as aminooxyacetic acid, BPTES, zaprinast, and chloroquinine in various cell types [67–70].
''IDH1'' mutation disables the decarboxylation reaction that converts αKG to isocitrate, a reaction important in hypoxic conditions where pyruvate influx from the TCA cycle is compromised and cells must use citrate and acetyl-CoA generated from glutamine and glutamate in order to maintain the ability to synthesise lipids[71]. In primary glioblastoma, where ''IDH1'' is overexpressed, knockdown of ''IDH1'' sensitises glioma-initiating cells with EGFR amplifications to erlotinib through decreased fatty acid and cholesterol synthesis[72].
''IDH1'' mutation disables the decarboxylation reaction that converts αKG to isocitrate, a reaction important in hypoxic conditions where pyruvate influx from the TCA cycle is compromised and cells must use citrate and acetyl-CoA generated from glutamine and glutamate in order to maintain the ability to synthesize lipids [71]. In primary glioblastoma, where ''IDH1'' is overexpressed, knockdown of ''IDH1'' sensitizes glioma-initiating cells with ''EGFR'' amplifications to erlotinib through decreased fatty acid and cholesterol synthesis [72].
2HG inhibits cytochrome c oxidase (complex IV of the ETC), preventing cytochrome c release into the mitochondrial matrix. This makes IDH mutated cells vulnerable to apoptosis through BAX/BAK mediated permeabilisation of the outer mitochondrial membrane, although normally this is prevented by BCL-2 binding to the BAX/BAK proapoptotic proteins[43,44]. Disrupting BCL-2 binding with venetoclax, a BH3 mimetic, results in apoptosis of IDH mutated cells but unmutated cells are relatively insensitive[73]. This has been observed in AML patients and glioblastoma models, though in the latter case BCL-xL appeared to be the primary target of the BH3 mimetic rather than BCL-2[44].
2HG inhibits cytochrome c oxidase (complex IV of the ETC), preventing cytochrome c release into the mitochondrial matrix. This makes ''IDH'' mutated cells vulnerable to apoptosis through BAX/BAK mediated permeabilisation of the outer mitochondrial membrane, although normally this is prevented by BCL-2 binding to the BAX/BAK proapoptotic proteins [43,44]. Disrupting BCL-2 binding with venetoclax, a BH3 mimetic, results in apoptosis of ''IDH'' mutated cells but unmutated cells are relatively insensitive [73]. This has been observed in AML patients and glioblastoma models, though in the latter case BCL-xL appeared to be the primary target of the BH3 mimetic rather than BCL-2 [44].
2HG downregulates nicotinate phosphoribosyltransferase (NAPRT1), which is an enzyme in the NAD+ salvage pathway. This leads to sensitivity to depletion of NAD+ in ''IDH1''-mutated cells by inhibition of nicotinamide phosphoribosyltransferase (NAMPT), another member of the pathway, with the preclinical compounds FK866 and GMX1778 leading to AMP kinase-initiated autophagy and cell death[45].
2HG downregulates nicotinate phosphoribosyltransferase (NAPRT1), which is an enzyme in the NAD+ salvage pathway. This leads to sensitivity to depletion of NAD+ in ''IDH1''-mutated cells by inhibition of nicotinamide phosphoribosyltransferase (NAMPT), another member of the pathway, with the preclinical compounds FK866 and GMX1778 leading to AMP kinase-initiated autophagy and cell death [45].
''IDH1''-mutated ICC cells depend on SRC kinase for mTOR mediated proliferation and survival. These cells are sensitive to dasatinib, a multikinase inhibitor with affinity for SRC[74].
''IDH1''-mutated ICC cells depend on SRC kinase for mTOR mediated proliferation and survival. These cells are sensitive to dasatinib, a multikinase inhibitor with affinity for SRC [74].
In AML, the ''IDH1'' Arg132His (NM_005896.2/NP_005887.2) mutant gene expression signature is indicative of a cellular phenotype that is responsive to treatment with small molecules targeting ROS and NAP+/NADPH signalling and metabolism[75].
In AML, the ''IDH1'' Arg132His (NM_005896.2/NP_005887.2) mutant gene expression signature is indicative of a cellular phenotype that is responsive to treatment with small molecules targeting ROS and NAP+/NADPH signalling and metabolism [75].
In pancreatic cancer cells, IDH1 has been linked to antioxidant defence as an adaptive strategy to cope with stress. Expression of ''IDH1'' is induced by HuR (Hu-Antigen R) after nutrient withdrawal or gemcitabine treatment. It has been suggested that this regulation is critical for pancreatic cancer cell survival under stress[76]. IDH1 mutations are rare in pancreatic cancer, however, probably owing to the importance of wild-type IDH1 function to pancreatic cancer cell survival.
In pancreatic cancer cells, ''IDH1'' has been linked to antioxidant defense as an adaptive strategy to cope with stress. Expression of ''IDH1'' is induced by HuR (Hu-Antigen R) after nutrient withdrawal or gemcitabine treatment. It has been suggested that this regulation is critical for pancreatic cancer cell survival under stress [76]. ''IDH1'' mutations are rare in pancreatic cancer, however, probably owing to the importance of wild-type IDH1 function to pancreatic cancer cell survival.
Mutant ''IDH1'' or ''IDH1'' knockdown radiosensitises cancerous and noncancerous cells[54,77], while ''IDH1'' overexpression is chemoprotective[78]. The radiosensitive phenotype of ''IDH1'' mutants is caused by both antioxidant depletion and impaired DNA damage response[54], the latter of which is associated with 2HG accumulation. The inhibition of ALKBH by 2HG also results in sensitisation of ''IDH1''-mutant cells to alkylating agents such as busulfan and CCNU[79], which provides an explanation for the sensitivity of ''IDH1''-mutated glioma to treatment with radiotherapy in the presence or absence of procarbazine, CCNU, and vincristine (the first two of which are alkylating agents)[80]. ''IDH1'' mutations also predict the response of glioblastoma to treatment with the DNA-alkylating agent temozolomide[81].
Mutant ''IDH1'' or ''IDH1'' knockdown radiosensitizes cancerous and noncancerous cells [54,77], while ''IDH1'' overexpression is chemoprotective [78]. The radiosensitive phenotype of ''IDH1'' mutants is caused by both antioxidant depletion and impaired DNA damage response [54], the latter of which is associated with 2HG accumulation. The inhibition of ALKBH by 2HG also results in sensitization of ''IDH1''-mutant cells to alkylating agents such as busulfan and CCNU [79], which provides an explanation for the sensitivity of ''IDH1''-mutated glioma to treatment with radiotherapy in the presence or absence of procarbazine, CCNU, and vincristine (the first two of which are alkylating agents) [80]. ''IDH1'' mutations also predict the response of glioblastoma to treatment with the DNA-alkylating agent temozolomide [81].
''IDH1''-mutated cancers are sensitive to PARP inhibitors, a phenotype that has been observed in AML and glioma[82,83], although the mechanism is unknown. Inhibition of the PARP-associated DNA repair pathway synergises with temozolomide in mutant glioma cells, and with daunorubicin in mutant AML, which suggests a treatment strategy that exploits the impaired DNA-repair pathway in ''IDH1''-mutants rather than using IDH1-mutant inhibitors may be beneficial[82]. In human cell models, a combination of ''IDH1'' mutation and ''ATM'' suppression caused sensitivity to irradiation and daunorubicin[82].
''IDH1''-mutated cancers are sensitive to PARP inhibitors, a phenotype that has been observed in AML and glioma [82,83], although the mechanism is unknown. Inhibition of the PARP-associated DNA repair pathway synergizes with temozolomide in mutant glioma cells, and with daunorubicin in mutant AML, which suggests a treatment strategy that exploits the impaired DNA-repair pathway in ''IDH1''-mutants rather than using ''IDH1''-mutant inhibitors may be beneficial [82]. In human cell models, a combination of ''IDH1'' mutation and ''ATM'' suppression caused sensitivity to irradiation and daunorubicin [82].
The fact that ''IDH1'' mutations arise very early in many cancers makes it an attractive therapeutic target, as the resulting tumour homogeneity decreases the risk of therapy resistance arising. IDH1-mutant inhibitors have been developed and show therapeutic promise in glioma, AML, and chondrosarcoma[84–87], although in AML these inhibitors may induce differentiation syndrome in some patients[88].
The fact that ''IDH1'' mutations arise very early in many cancers makes it an attractive therapeutic target, as the resulting tumor homogeneity decreases the risk of therapy resistance arising. ''IDH1''-mutant inhibitors have been developed and show therapeutic promise in glioma, AML, and chondrosarcoma [84–87], although in AML these inhibitors may induce differentiation syndrome in some patients [88].
==Common Alteration Types==
==Common Alteration Types==
Gain-of-function mutations in ''IDH1'' include:
c.395G>A, p.R132H
(NM_005896.2/NP_005887.2)
c.394C>T, p.R132C
(NM_005896.2/NP_005887.2)
c.394C>G, p.R132G
(NM_005896.2/NP_005887.2)
c.394C>A, p.R132S
(NM_005896.2/NP_005887.2)
c.395G>T, p.R132L
(NM_005896.2/NP_005887.2)
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
! Copy Number Loss !! Copy Number Gain !! LOH !! Loss-of-Function Mutation !! Gain-of-Function Mutation !! Translocation/Fusion
! Copy Number Loss !! Copy Number Gain !! LOH !! Loss-of-Function Mutation !! Gain-of-Function Mutation !! Translocation/Fusion
|-
|-
| EXAMPLE: X ||EXAMPLE: X || EXAMPLE: X || EXAMPLE: X || EXAMPLE: X || EXAMPLE: X
| || || || || X ||
|}
|}
==External Links==
==External Links==
'''[http://atlasgeneticsoncology.org/Genes/GC_IDH1.html ''IDH1'' by Atlas of Genetics and Cytogenetics in Oncology and Haematology]''' - detailed gene information
'''[https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=IDH1 ''IDH1'' by COSMIC]''' - sequence information, expression, catalogue of mutations
'''[https://civicdb.org/events/genes/26/summary/variants/645/summary ''IDH1'' by CIViC]''' - general knowledge and evidence-based variant specific information
'''[https://pecan.stjude.cloud/proteinpaint/idh1 ''IDH1'' by St. Jude ProteinPaint]''' mutational landscape and matched expression data.
'''[https://pmkb.weill.cornell.edu/search?utf8=✓&search=idh1 ''IDH1'' by Precision Medicine Knowledgebase (Weill Cornell)]''' - manually vetted interpretations of variants and CNVs
'''[http://www.cancerindex.org/geneweb/IDH1.htm ''IDH1'' by Cancer Index]''' - gene, pathway, publication information matched to cancer type
'''[http://oncokb.org/#/gene/IDH1 ''IDH1'' by OncoKB]''' - mutational landscape, mutation effect, variant classification
'''[https://www.mycancergenome.org/content/gene/idh1/ ''IDH1'' by My Cancer Genome]''' - brief gene overview
'''[https://www.uniprot.org/uniprot/O75874 ''IDH1'' by UniProt]''' - protein and molecular structure and function
'''[https://pfam.xfam.org/family/PF00180 ''IDH1'' by Pfam]''' - gene and protein structure and function information
'''[https://www.genecards.org/cgi-bin/carddisp.pl?gene=IDH1&keywords=idh1 ''IDH1'' by GeneCards]''' - general gene information and summaries
==References==
1. Jennings GT, et al., (1994). Cytosolic NADP (+)-dependent isocitrate dehydrogenase. Isolation of rat cDNA and study of tissue-specific and developmental expression of mRNA. J Biol Chem 269:23128–23134, PMID 8083215.
2. Yoshihara T, et al., (2001). Localization of cytosolic NADP-dependent isocitrate dehydrogenase in the peroxisomes of rat liver cells: biochemical and immunocytochemical studies. J Histochem Cytochem 49:1123–1131, PMID 11511681.
3. Xu X, et al., (2004). Structures of Human Cytosolic NADP-dependent Isocitrate Dehydrogenase Reveal a Novel Self-regulatory Mechanism of Activity. J Biol Chem 279:33946–33957, PMID 15173171.
4. Zhao S, et al., (2009). Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1α. Science 324:261–265, PMID 19359588.
5. Khurshed M, et al., (2017). In silico gene expression analysis reveals glycolysis and acetate anaplerosis in IDH1 wild-type glioma and lactate and glutamate anaplerosis in IDH1-mutated glioma. Oncotarget 8(30):49165-49177, PMID 28467784.
6. Bleeker FE, et al., (2010). The prognostic IDH1 R132 mutation is associated with reduced NADP+-dependent IDH activity in glioblastoma. Acta Neuropathol (Berl) 119:487–494, PMID 20127344.
7. Minard KI and McAlister-Henn L, (1999). Dependence of peroxisomal β-oxidation on cytosolic sources of NADPH. J Biol Chem 274:3402–3406, PMID 9920883.
8. Mailloux R J, et al., (2007). The tricarboxylic acid cycle, an ancient metabolic network with a novel twist. PLoS ONE 2:e690, PMID 17668068.
9. Lee SM, et al., (2002). Cytosolic NADP+-dependent isocitrate dehydrogenase status modulates oxidative damage to cells. Free Radic. Biol Med 32:1185–1196, PMID 12031902.
10. Yang ES, et al., (2010). Silencing of cytosolic NADP+-dependent isocitrate dehydrogenase gene enhances ethanol-induced toxicity in HepG2 cells. Arch Pharm Res 33:1065–1071, PMID 20661717.
11. Lee S‐H, et al., (2004). Role of NADP + ‐dependent isocitrate dehydrogenase (NADP + ‐ICDH) on cellular defence against oxidative injury by γ ‐rays. Int J Radiat Biol 80:635–642, PMID 15586883.
12. Jo S-H, et al., (2002). Cellular defense against UVB-induced phototoxicity by cytosolic NADP+-dependent isocitrate dehydrogenase. Biochem Biophys Res Commun 292:542–549, PMID 11906195.
13. Lee SM, et al., (2001). Inactivation of NADP+-dependent isocitrate dehydrogenase by reactive oxygen species. Biochimie 83:1057–1065, PMID 11879734.
14. Batinic-Haberle I and Benov LT, (2008). An SOD mimic protects NADP + -dependent isocitrate dehydrogenase against oxidative inactivation. Free Radic Res 42:618–624, PMID 18608518.
15. Shechter I, et al, (2003). IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells: evidence that IDH1 may regulate lipogenesis in hepatic cells. J Lipid Res 44:2169–2180, PMID 12923220.
16. Joseph JW, et al., (2006). The mitochondrial citrate/isocitrate carrier plays a regulatory role in glucose-stimulated insulin secretion. J Biol Chem 281:35624–35632, PMID 17001083.
17. Koh H-J, et al., (204). Cytosolic NADP + -dependent isocitrate dehydrogenase plays a key role in lipid metabolism. J Biol Chem 279:39968–39974, PMID 15254034.
18. Ronnebaum SM, et al., (2006). A pyruvate cycling pathway involving cytosolic NADP-dependent isocitrate dehydrogenase regulates glucose-stimulated insulin secretion. J Biol Chem 281:30593–30602, PMID 16912049.
19. Reitman ZJ and Yan H, (2010). Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J Natl Cancer Inst 102:932–941, PMID 20513808.
20. Yan H, et al., (2009). IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773, PMID 23532369.
21. Sanson M, et al., (2009). Isocitrate dehydrogenase 1 Codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 27:4150–4154, PMID 19636000.
22. Nobusawa S, et al., (2009). IDH1 mutations as molecular signature and predictive factor of secondary glioblastomas. Clin Cancer Res 15:6002–6007, PMID 19755387.
23. Lugowska I, et al., (2018). IDH1/2 mutations predict shorter survival in chondrosarcoma. J Cancer 9:998–1005, PMID 29581779.
24. Amary MF, et al., (2011). IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol 224:334–343, PMID 21598255.
25. Pansuriya TC, et al., (2011). Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet 43:1256–1261, PMID 22057234.
26. Wang P, et al., (2013). Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene 32:3091–3100, PMID 22824796.
27. Borger DR, et al., (2012). Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. The Oncologist 17:72–79, PMID 22180306.
28. Churi CR, et al., (2014). Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications. PLOS ONE 9:e115383, PMID 25536104.
29. Goyal L, et al., (2015). Prognosis and clinicopathologic features of patients with advanced stage isocitrate dehydrogenase (IDH) mutant and IDH wild-type intrahepatic cholangiocarcinoma. The Oncologist 20:1019–1027, PMID 26245674.
30. Jiao Y, et al., (2013). Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet 45:1470–1473, PMID 24185509.
31. Mardis ER, et al., (2009). Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 361:1058–1066, PMID 19657110.
32. Xu Q, et al., (2017. Correlation between isocitrate dehydrogenase gene aberrations and prognosis of patients with acute myeloid leukemia: a systematic review and meta-analysis. Clin Cancer Res 23:4511–4522, PMID 28246275.
33. Schnittger S, et al., (2010). IDH1 mutations are detected in 6.6% of 1414 AML patients and are associated with intermediate risk karyotype and unfavorable prognosis in adults younger than 60 years and unmutated NPM1 status. Blood 116:5486–5496, PMID 20805365.
34. Patnaik MM, et al., (2012). Differential prognostic effect of IDH1 versus IDH2 mutations in myelodysplastic syndromes: a Mayo Clinic Study of 277 patients. Leukemia 26:101–105, PMID 22033490.
35. Schumacher T, et al., (2014). A vaccine targeting mutant IDH1 induces antitumour immunity. Nature 512:324, PMID 25043048.
36. Farshidfar F, et al., (2017). Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles. Cell Rep 18:2780–2794, PMID 28658632.
37. Papaemmanuil E, et al., 2016. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med 374:2209–2221, PMID 27276561.
38. Molenaar RJ, et al., (2015). Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms. Leukemia 29:2134, PMID 25836588.
39. Dang L, et al., (2009). Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739–744, PMID 19935646.
40. Molenaar RJ, et al., (2018). Wild-type and mutated IDH1/2 enzymes and therapy responses. Oncogene 37:1949–1960, PMID 29367755.
41. Gatenby RA and Gillies RJ, (2004). Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4:891–899, PMID 15516961.
42. Frezza C, et al., (2010). IDH1 mutations in gliomas: when an enzyme loses its grip. Cancer Cell 17:7–9, PMID 20129244.
43. Chan SM, et al., (2015). Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med 21:178–184, PMID 25599133.
44. Karpel-Massler G, et al., (2017). Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL. Nat Commun 8(2):1067, PMID 29057925.
45. Tateishi K, et al., (2015). Extreme vulnerability of IDH1 mutant cancers to NAD+ depletion. Cancer Cell 28:773–784, PMID 26678339.
46. Chen F, et al., (2017). Oncometabolites D - and L -2-Hydroxyglutarate inhibit the AlkB family DNA repair enzymes under physiological conditions. Chem Res Toxicol 30:1102–1110, PMID 28269980.
47. Sulkowski PL, et al., (2017). 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci Transl Med 9:eaal2463, PMID 28148839.
48. Inoue S, et al., (2016). Mutant IDH1 downregulates ATM and alters DNA repair and sensitivity to DNA damage independent of TET2. Cancer Cell 30:337–348, PMID 27424808.
49. Noushmehr H,et al., (201). Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17:510–522, PMID 20399149.
50. Figueroa ME, et al., (2010). Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18:553–567, PMID 21130701.
51. Turcan S, et al., (2012). IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483:479–483, PMID 22343889.
52. Losman J-A and Kaelin WG, (2013). What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev 27:836–852, PMID 23630074.
53. Tönjes M, et al., (2013). BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat Med 19:901–908, PMID 23793099.
54. Molenaar RJ, et al., (2015). Radioprotection of IDH1-mutated cancer cells by the IDH1-mutant inhibitor AGI-5198. Cancer Res 75:4790–4802, PMID 26363012.
55. Shi J, et al., (2015). Decreasing GSH and increasing ROS in chemosensitivity gliomas with IDH1 mutation. Tumor Biol 36:655–662, PMID 25283382.
56. Molenaar RJ, et al., (2014). The driver and passenger effects of isocitrate dehydrogenase 1 and 2 mutations in oncogenesis and survival prolongation. Biochim Biophys Acta BBA-Rev Cancer 1846:326–341, PMID 24880135.
57. Gilbert MR, et al., (2014). Autophagy and oxidative stress in gliomas with IDH1 mutations. Acta Neuropathol (Berl) 127:221–233, PMID 24150401.
58. Ohgaki H and Kleihues P, (2009). Genetic alterations and signaling pathways in the evolution of gliomas. Cancer Sci 100:2235–2241, PMID 19737147.
59. Watanabe T, et al., (2009). IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol 174:1149–1153, PMID 19246647.
60. Watanabe T, et al., (2009). Selective acquisition of IDH1 R132C mutations in astrocytomas associated with Li-Fraumeni syndrome. Acta Neuropathol (Berl) 117:653–656, PMID 19340432.
61. The Cancer Genome Atlas Research Network. Comprehensive, (2015).Integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 372:2481–2498, PMID 26061751.
62. Chou W-C, et al., (2011). The prognostic impact and stability of Isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia. Leukemia 25:246–253, PMID 21079611.
63. Marcucci G, et al., (2010). IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol 28:2348–2355, PMID 20368543.
64. Feng J-H, et al., (2012). Prognostic significance of IDH1 mutations in acute myeloid leukemia: a meta-analysis. Am J Blood Res 2:254, PMID 23226625.
65. Cuyàs E, et al., (2015). Oncometabolic mutation IDH1 R132H confers a metformin-hypersensitive phenotype. Oncotarget 6(14):12279-12296, PMID 25980580.
66. Molenaar RJ, et al., (2017). Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with IDH1 -mutated or IDH2 -mutated solid tumours. BMJ Open 7:e014961, PMID 28601826.
67. Seltzer MJ, et al., (2010). Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Res 70:8981–8987, PMID 21045145.
68. Elhammali A, et al., (2014). A high-throughput fluorimetric assay for 2-Hydroxyglutarate identifies zaprinast as a glutaminase inhibitor. Cancer Discov 4:828–839, PMID 24740997.
69. Emadi A, et al., (2014). Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutations. Exp Hematol 42:247–251, PMID 24333121.
70. Mohrenz IV, et al., (2013). Isocitrate dehydrogenase 1 mutant R132H sensitizes glioma cells to BCNU-induced oxidative stress and cell death. Apoptosis 18:1416–1425, PMID: 23801081.
71. Metallo CM, et al., (2012). Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481:380–384, PMID 22101433.
72. Calvert AE, et al., (2017). Cancer-associated IDH1 promotes growth and resistance to targeted therapies in the absence of mutation. Cell Rep 19:1858–1873, PMID 28564604.
73. Konopleva M, et al., (2016). Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov 6:1106–1117, PMID 27520294.
74. Saha SK, et al., (2016). Isocitrate dehydrogenase mutations confer dasatinib hypersensitivity and SRC dependence in intrahepatic cholangiocarcinoma. Cancer Discov 6:727–739, PMID 27231123.
75. Boutzen H, et al., (2016). Isocitrate dehydrogenase 1 mutations prime the all-trans retinoic acid myeloid differentiation pathway in acute myeloid leukemia. J Exp Med 213:483–497, PMID 26951332.
76. Zarei M, et al., (2017). Posttranscriptional upregulation of IDH1 by HuR establishes a powerful survival phenotype in pancreatic cancer cells. Cancer Res 77:4460–4471, PMID 28652247.
77. Kim SY, et al., (2013). Silencing of mitochondrial NADP+-dependent isocitrate dehydrogenase gene enhances glioma radiosensitivity. Biochem Biophys Res Commun 433:260–265, PMID 23500467.
78. Wang J-B, et al., (2014). IDH1 overexpression induced chemotherapy resistance and IDH1 mutation enhanced chemotherapy sensitivity in glioma cells in vitro and in vivo. Asian Pac J Cancer Prev 15:427–432, PMID 24528069.
79. Wang P, et al., (2015). Oncometabolite D-2-Hydroxyglutarate inhibits ALKBH DNA repair enzymes and sensitizes IDH mutant cells to alkylating agents. Cell Rep 13:2353–2361, PMID 26686626.
80. Buckner JC, et al., (2016). Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med 374:1344–1355, PMID 27050206.
81. SongTao Q, et al., (2012). IDH mutations predict longer survival and response to temozolomide in secondary glioblastoma. Cancer Sci 103:269–273, PMID 22034964.
82. Molenaar RJ, et al., (2018). IDH1/2 mutations sensitize acute myeloid leukemia to PARP inhibition and this is reversed by IDH1/2-mutant inhibitors. Clin Cancer Res 24:1705–1715, PMID 29339439.
83. Lu Y, et al., (2017). Chemosensitivity of IDH1-mutated gliomas due to an impairment in PARP1-mediated DNA repair. Cancer Res 77:1709–1718, PMID 28202508.
84. Popovici-Muller J, et al., (2012). Discovery of the first potent inhibitors of mutant IDH1 that lower tumor 2-HG in vivo. ACS Med Chem Lett 3:850–855, PMID 24900389.
85. Popovici-Muller J, et al., (2018). Discovery of AG-120 (ivosidenib): a first-in-class mutant IDH1 inhibitor for the treatment of IDH1 mutant cancers. ACS Med Chem Lett 9:300–305, PMID 29670690.
86. Rohle D, et al., (2013). An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340:626–630, PMID 23558169.
87. Li L, et al., (2015). Treatment with a small molecule mutant IDH1 inhibitor suppresses tumorigenic activity and decreases production of the oncometabolite 2-Hydroxyglutarate in human chondrosarcoma cells. PLOS ONE 10:e0133813, PMID 26368816.
88. Birendra KC and DiNardo CD, (2016). Evidence for clinical differentiation and differentiation syndrome in patients with acute myeloid leukemia and IDH1 mutations treated with the targeted mutant IDH1 inhibitor, AG-120. Clin Lymphoma Myeloma Leuk 16:460–465, PMID 27245312.
== Notes ==
== Notes ==