Changes

===Structure and function===

===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 IDH1 is localised to the cytoplasm and in peroxisomes, IDH2 and IDH3 are mitochondrial.  

''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 IDH1 is localised to the cytoplasm and in peroxisomes, IDH2 and IDH3 are mitochondrial.  

NADP+-dependent isocitrate dehydrogenases function as homodimers to catalyse the reversible NADP-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 NADP-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.

''IDH2'' is highly expressed in mammalian heart and muscle tissue and in activated lymphocytes, with moderate expression elsewhere[1,2]. The IDH2 protein contains an N-terminal mitochondrial signal peptide, which allows for its mitochondrial localisation[3]. Less is known about the structure of human IDH2 than of IDH1, although studies on porcine IDH2 indicate that they are largely similar[4]. Both IDH1 and IDH2 function by combining two IDH subunits to create binding sites for the substrate along with NADP+ and a metal ion[4]. Crucially, the Arg172 (NM_002168.2/NP_002159.2) residue of IDH2 demonstrates similar functional importance as the equivalent Arg132 (NM_005896.2/NP_005887.2) residue of IDH1[3,4]. In IDH2 the Arg140 (NM_002168.2/NP_002159.2) residue situated adjacent to Arg172 in the active site additionally forms hydrogen bonds with the isocitrate substrate, and so likely also plays an important functional role[5].

''IDH2'' is highly expressed in mammalian heart and muscle tissue and in activated lymphocytes, with moderate expression elsewhere [1,2]. The IDH2 protein contains an N-terminal mitochondrial signal peptide, which allows for its mitochondrial localization [3]. Less is known about the structure of human ''IDH2'' than of ''IDH1'', although studies on porcine ''IDH2'' indicate that they are largely similar [4]. Both ''IDH1'' and ''IDH2'' function by combining two ''IDH'' subunits to create binding sites for the substrate along with NADP+ and a metal ion [4]. Crucially, the Arg172 (NM_002168.2/NP_002159.2) residue of ''IDH2'' demonstrates similar functional importance as the equivalent Arg132 (NM_005896.2/NP_005887.2) residue of ''IDH1'' [3,4]. In ''IDH2'', the Arg140 (NM_002168.2/NP_002159.2) residue situated adjacent to Arg172 in the active site additionally forms hydrogen bonds with the isocitrate substrate, and so likely also has an important functional role [5].

IDH2 plays a role in the regulation of oxidative respiration in multiple tissues. There is evidence that in the heart and in glioma cells IDH2 regulates the TCA cycle by reverse flux, catalysing the conversion of αKG and NADPH to isocitrate and NADP+[5,6]. This has led to the proposal of an isocitrate/αKG cycle wherein IDH2 functions in the reverse direction and IDH3 in the forward (i.e. isocitrate to αKG), thereby maintaining tight control of flux through the TCA cycle[7,8].

''IDH2'' plays a role in the regulation of oxidative respiration in multiple tissues. There is evidence that in the heart and in glioma cells, IDH2 regulates the TCA cycle by reverse flux, catalysing the conversion of αKG and NADPH to isocitrate and NADP+ [5,6]. This has led to the proposal of an isocitrate/αKG cycle wherein IDH2 functions in the reverse direction and IDH3 in the forward (i.e. isocitrate to αKG), thereby maintaining tight control of flux through the TCA cycle [7,8].

NADP+-dependent isocitrate dehydrogenases are upregulated after oxidative insult and can modulate the availability of αKG, itself a potent antioxidant[9]. Overexpression of ''IDH2'' confers protection against oxidative DNA damage and increases survival after oxidant exposure, implicating it in the same oxidative defence pathways as ''IDH1''[10]. IDH2 also protects against ionising radiation[11,12], exposure to high glucose[13], treatment with tumour necrosis factor-alpha (TNF-α)[14], and apoptosis induced by heat-shock[13].

NADP+-dependent isocitrate dehydrogenases are upregulated after oxidative insult and can modulate the availability of αKG, itself a potent antioxidant [9]. Overexpression of ''IDH2'' confers protection against oxidative DNA damage and increases survival after oxidant exposure, implicating it in the same oxidative defence pathways as ''IDH1''[10]. IDH2 also protects against ionising radiation [11,12], exposure to high glucose [13], treatment with tumor necrosis factor-alpha (TNF-α) [14], and apoptosis induced by heat-shock [13].

Germline mutations in ''IDH2'' are rare, but result in D-2-hydroxyglutaric aciduria, which can cause developmental delay, epilepsy, and cardiomyopathy, among other presentations[15].

Germline mutations in ''IDH2'' are rare, but result in D-2-hydroxyglutaric aciduria, which can cause developmental delay, epilepsy, and cardiomyopathy, among other presentations [15].

===Role in Cancer===

===Role in Cancer===

''IDH2'' mutations are seen much less frequently in glioma than ''IDH1'' mutations, with a frequency of 0-3% in grade 2 and 3 glioma and secondary glioblastoma[8,16]. ''IDH1'' and ''IDH2'' mutations in these malignancies are often mutually exclusive, suggesting overlapping pathogenic effects[16,17]. ''IDH2'' mutations are also seen at low frequency in other solid tumours including chondrosarcoma and intrahepatic cholangiocarcinoma (ICC)[18,19]. Like ''IDH1'' mutations, mutations in ''IDH2'' are associated with a younger age at diagnosis in adults and improved survival relative to wild-type ''IDH2'' in glioma, presumably due to increased sensitivity to therapy[16,20]. However, ''IDH2'' mutations predict decreased overall survival in chondrosarcoma[21].

''IDH2'' mutations are seen much less frequently in glioma than ''IDH1'' mutations, with a frequency of 0-3% in grade 2 and 3 glioma and secondary glioblastoma [8,16]. ''IDH1'' and ''IDH2'' mutations in these malignancies are often mutually exclusive, suggesting overlapping pathogenic effects [16,17]. ''IDH2'' mutations are also seen at low frequency in other solid tumors including chondrosarcoma and intrahepatic cholangiocarcinoma (ICC) [18,19]. Like ''IDH1'' mutations, alterations in ''IDH2'' are associated with a younger age at diagnosis in adults and improved survival relative to wild-type ''IDH2'' in glioma, presumably due to increased sensitivity to therapy [16,20]. However, ''IDH2'' mutations predict decreased overall survival in chondrosarcoma [21].

The frequency of ''IDH2'' mutations in AML is higher, with studies indicating mutation rates of up to 15%[8,22]. The younger diagnostic age seen in ''IDH2''-mutated glioma appears to hold true for AML in adult patients, but the prognostic impact of ''IDH2'' mutations is unclear and may depend on the specific mutation, with Arg140 (NM_002168.2/NP_002159.2) mutations having more favourable prognostic outlook than Arg172 (NM_002168.2/NP_002159.2) mutations[23–26].  

The frequency of ''IDH2'' mutations in AML is higher, with studies indicating mutation rates of up to 15% [8,22]. The younger diagnostic age seen in ''IDH2''-mutated glioma appears to hold true for AML in adult patients, but the prognostic impact of ''IDH2'' mutations is unclear and may depend on the specific mutation, with Arg140 (NM_002168.2/NP_002159.2) mutations having more favorable prognostic outlook than Arg172 (NM_002168.2/NP_002159.2) mutations [23–26].  

IDH2 R172 mutations also appear in approximately 20% of angioimmunoblastic T-cell lymphomas (AITL) (but not in other lymphomas), although they do not appear to provide prognostic information[27]. In AITL IDH2 R172 mutations define a subgroup with a distinct gene expression signature, and when paired with ''TET2'' mutations correlate with a gene expression profile indicative of a T follicular helper cell (TFH) phenotype rather than that of other T helper cells, possibly through downregulation of non-TFH differentiation genes[28].

''IDH2'' R172 mutations also appear in approximately 20% of angioimmunoblastic T-cell lymphomas (AITL) (but not in other lymphomas), although they do not provide prognostic information [27]. In AITL, ''IDH2'' R172 mutations define a subgroup with a distinct gene expression signature, and when paired with ''TET2'' mutations correlate with a gene expression profile indicative of a T follicular helper cell (TFH) phenotype rather than that of other T helper cells, possibly through downregulation of non-TFH differentiation genes [28].

IDH2 mutations in cancer are almost invariably heterozygous mutations affecting the Arg172 residue, except in AML where mutations in Arg140 have also been observed[5,8,16]. Like in IDH1 Arg132 (NM_005896.2/NP_005887.2) mutations, mutations in IDH2 Arg172 decrease enzyme affinity for isocitrate and hence reduce NADPH production16,29. IDH2 R172 and IDH2 R140 mutations result in the same neomorphic enzyme activity as the IDH1 R132 mutant, whereby αKG is reduced to D-2-hydroxyglutarate (2HG)[5,30].

''IDH2'' mutations in cancer are almost invariably heterozygous affecting the Arg172 residue, except in AML where mutations in Arg140 have also been observed [5,8,16]. Like in ''IDH1'' Arg132 (NM_005896.2/NP_005887.2) mutations, alterations in ''IDH2'' Arg172 decrease enzyme affinity for isocitrate and hence reduce NADPH production [16,29]. ''IDH2'' R172 and ''IDH2'' R140 mutations result in the same neomorphic enzyme activity as the ''IDH1'' R132 mutant, whereby αKG is reduced to D-2-hydroxyglutarate (2HG) [5,30].

Studies on IDH1 R132 mutants have shown impaired TCA cycle flux under hypoxic conditions, but this doesn’t appear to hold true for ''IDH2'' mutants[31]. ''IDH2'' mutants are, however, affected by the same sensitivity to BAX/BAK-mediated apoptosis[32]. ''IDH2'' mutants also have the same widespread hypermethylation found in ''IDH1'' mutants[22,33]. This is likely caused by 2HG inhibition of αKG-dependent proteins such as the alkB homolog (ALKBH) DNA repair enzyme, the lysine-specific demethylase 4A/B (KDM4A/B) DNA damage response proteins, and the methylcytosine dioxygenase TET2[34,35]. IDH2-mutant cells show also reduced expression of the DNA damage response gene ''ATM'' and, predictably, increased levels of DNA damage[35,36].

Studies on ''IDH1'' R132 mutants have shown impaired TCA cycle flux under hypoxic conditions, but this doesn’t appear to hold true for ''IDH2'' mutants [31]. ''IDH2'' mutants are, however, affected by the same sensitivity to BAX/BAK-mediated apoptosis [32]. ''IDH2'' mutants also have the same widespread hypermethylation found in ''IDH1'' mutants [22,33]. This is likely caused by 2HG inhibition of αKG-dependent proteins such as the alkB homolog (ALKBH) DNA repair enzyme, the lysine-specific demethylase 4A/B (KDM4A/B) DNA damage response proteins, and the methylcytosine dioxygenase TET2 [34,35]. ''IDH2''-mutant cells show also reduced expression of the DNA damage response gene ''ATM'' and, predictably, increased levels of DNA damage [35,36].

===Concurrent Mutations===

===Concurrent Mutations===

Due to the infrequency of ''IDH2'' mutations relative to ''IDH1'' mutations in glioma, less data exists for concurrent or cooperating mutations. As mentioned, ''IDH1'' and ''IDH2'' mutations often occur in a mutually exclusive manner. ''IDH2''-mutants in glioma appear to show the same pattern of concurrent mutations as do ''IDH1''-mutants, demonstrating increased association with ''TP53'' mutations and lowered association with mutations in other genes 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[16].

Due to the infrequency of ''IDH2'' mutations relative to ''IDH1'' mutations in glioma, less data exists for concurrent or cooperating mutations. As mentioned, ''IDH1'' and ''IDH2'' mutations often occur in a mutually exclusive manner. ''IDH2''-mutants in glioma appear to show the same pattern of concurrent mutations as do ''IDH1''-mutants, demonstrating increased association with ''TP53'' mutations and lowered association with mutations in other genes 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 [16].

In AML, where ''IDH2'' mutations are more prevalent, most ''IDH2''-mutant patients have at least one other concurrent mutation in a pathogenic gene[24]. ''IDH2''-mutant AML has a lower incidence of ''WT1'' mutations, a positive association with ''NPM1'' mutations, and a negative association with ''CEBPA'' mutations, although these genetic lesions are much more commonly found concomitantly with IDH2 Arg140 (NM_002168.2/NP_002159.2) mutants than with Arg172 (NM_002168.2/NP_002159.2) mutants[23,24]. There is greater incidence of ''IDH2'' mutations in patients with cytogenetically normal or intermediate-risk AML as well as isolated trisomy 8, but lower association in patients with core-binding factor AML or t(15;17)[23,24]. ''TET2'' mutations occur at high frequency in AML but are mutually exclusive with ''IDH2'' mutations, consistent with the notion that ''TET2'' inhibition is a pathogenic factor in ''IDH2'' mutant AML[22]. In AITL, however, ''IDH2'' and ''TET2'' mutations are commonly found together[28].

In AML, where ''IDH2'' mutations are more prevalent, most ''IDH2''-mutant patients have at least one other concurrent mutation in a pathogenic gene [24]. ''IDH2''-mutant AML has a lower incidence of ''WT1'' mutations, a positive association with ''NPM1'' mutations, and a negative association with ''CEBPA'' mutations, although these genetic lesions are much more commonly found concomitantly with IDH2 Arg140 (NM_002168.2/NP_002159.2) mutants than with Arg172 (NM_002168.2/NP_002159.2) mutants [23,24]. There is greater incidence of ''IDH2'' mutations in patients with cytogenetically normal or intermediate-risk AML as well as isolated trisomy 8, but lower association in patients with core-binding factor AML or AML with t(15;17)[23,24]. ''TET2'' mutations occur at high frequency in AML but are mutually exclusive with ''IDH2'' mutations, consistent with the notion that ''TET2'' inhibition is a pathogenic factor in ''IDH2'' mutant AML [22]. In AITL, however, ''IDH2'' and ''TET2'' mutations are commonly found together [28].

===Therapeutic Implications===

===Therapeutic Implications===

In ICC cells, ''IDH2'' mutations confer sensitivity to the multikinase inhibitor dasatinib due to their dependence on the kinase SRC for mTOR-mediated proliferation[37]. Overexpression of mutant ''IDH2'' in glioblastoma cells increases their sensitivity to radiation[38].

In ICC cells, ''IDH2'' mutations confer sensitivity to the multikinase inhibitor dasatinib due to their dependence on the kinase SRC for mTOR-mediated proliferation [37]. Overexpression of mutant ''IDH2'' in glioblastoma cells increases their sensitivity to radiation [38].

An IDH2-mutant inhibitor, enasidenib, suppresses 2HG production, reverses epigenetic dysregulation, and induces cellular differentiation in ''IDH2''-mutated AML. It has shown response rates of approximately 40% in relapsed and refractory AML patients and a remission rate of 19%[39]. ''IDH2''-mutant AML is also more susceptible to venetoclax therapy owing to increased sensitivity to BAX/BAK-mediated apoptosis[40]. In-vitro studies show ''IDH2''-mutant AML is sensitised to radiation, daunorubicin, and the PARP inhibitors olaparib and talazoparib; these phenotypes are reversed by treatment with IDH2-mutant inhibitor[36], suggesting that there may be some benefit in exploiting rather than diminishing the effect of ''IDH2'' mutations in certain malignancies.

An ''IDH2''-mutant inhibitor, enasidenib, suppresses 2HG production, reverses epigenetic dysregulation, and induces cellular differentiation in ''IDH2''-mutated AML. It has shown response rates of approximately 40% in relapsed and refractory AML patients and a remission rate of 19% [39]. ''IDH2''-mutant AML is also more susceptible to venetoclax therapy owing to increased sensitivity to BAX/BAK-mediated apoptosis [40]. ''In vitro'' studies show ''IDH2''-mutant AML is sensitized to radiation, daunorubicin, and the PARP inhibitors olaparib and talazoparib; these phenotypes are reversed by treatment with ''IDH2''-mutant inhibitor [36], suggesting that there may be some benefit in exploiting rather than diminishing the effect of ''IDH2'' mutations in certain malignancies.

==Common Alteration Types==

==Common Alteration Types==