IDH1

Primary Author(s)*

Paul De Fazio, MSc, Monash Health

Synonyms

Isocitrate Dehydrogenase NADP(+) 1 Cytosolic, Isocitrate Dehydrogenase 1 (NADP+) Soluble, Oxalosuccinate Decarboxylase, NADP(+)-Specific ICDH, PICD, IDH, IDP, NADP-Dependent Isocitrate Dehydrogenase Peroxisomal, NADP-Dependent Isocitrate Dehydrogenase Cytosolic, Isocitrate Dehydrogenase [NADP] Cytoplasmic, Cytosolic NADP-Isocitrate Dehydrogenase, Isocitrate Dehydrogenase 1 (NADP+), Epididymis Secretory Protein Li 26, Epididymis Luminal Protein 216, HEL-S-26, HEL-216, IDCD, IDPC

Genomic Location

Cytoband: 2q34

Genomic Coordinates:

chr2:209,100,951-209,130,798 [hg19]

chr2:208,236,227-208,266,074 [hg38]

Cancer Category/Type

Glioma, astrocytoma, oligodendroglioma, acute myeloid leukaemia, myelodysplastic syndrome, lymphoma, prostate cancer, thyroid cancer

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.

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.

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].

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].

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.

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].

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].

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].

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].

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.

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].

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].

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].

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.

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].

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].

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].

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].

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 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.

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].

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].

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].

Common Alteration Types

Put your text here and/or fill in the table with an X where applicable

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

Internal Pages

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EXAMPLE Germline Cancer Predisposition Genes

External Links

Put your text here - Include as applicable links to: 1) Atlas of Genetics and Cytogenetics in Oncology and Haematology, 2) COSMIC, 3) CIViC, 4) St. Jude ProteinPaint, 5) Precision Medicine Knnowledgebase (Weill Cornell), 6) Cancer Index, 7) OncoKB, 8) My Cancer Genome, 9) UniProt, 10) Pfam, 11) GeneCards, 12) GeneReviews, and 13) Any gene-specific databases.

EXAMPLES

TP53 by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information

TP53 by COSMIC - sequence information, expression, catalogue of mutations

TP53 by CIViC - general knowledge and evidence-based variant specific information

TP53 by IARC - TP53 database with reference sequences and mutational landscape

TP53 by St. Jude ProteinPaint mutational landscape and matched expression data.

TP53 by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs

TP53 by Cancer Index - gene, pathway, publication information matched to cancer type

TP53 by OncoKB - mutational landscape, mutation effect, variant classification

TP53 by My Cancer Genome - brief gene overview

TP53 by UniProt - protein and molecular structure and function

TP53 by Pfam - gene and protein structure and function information

TP53 by GeneCards - general gene information and summaries

GeneReviews - information on Li Fraumeni Syndrome

References

EXAMPLE Book

1. Arber DA, et al., (2008). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Editors. IARC Press: Lyon, France, p117-118.

EXAMPLE Journal Article

1. Li Y, et al., (2001). Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nat Genet 28:220-221, PMID 11431691.

Notes

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