Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations

Abstract

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), are present in most gliomas and secondary glioblastomas, but are rare in other neoplasms. IDH1/2 mutations are heterozygous, and affect a single arginine residue. Recently, IDH1 mutations were identified in 8% of acute myelogenous leukemia (AML) patients. A glioma study revealed that IDH1 mutations cause a gain-of-function, resulting in the production and accumulation of 2-hydroxyglutarate (2-HG). Genotyping of 145 AML biopsies identified 11 IDH1 R132 mutant samples. Liquid chromatography-mass spectrometry metabolite screening revealed increased 2-HG levels in IDH1 R132 mutant cells and sera, and uncovered two IDH2 R172K mutations. IDH1/2 mutations were associated with normal karyotypes. Recombinant IDH1 R132C and IDH2 R172K proteins catalyze the novel nicotinamide adenine dinucleotide phosphate (NADPH)–dependent reduction of α-ketoglutarate (α-KG) to 2-HG. The IDH1 R132C mutation commonly found in AML reduces the affinity for isocitrate, and increases the affinity for NADPH and α-KG. This prevents the oxidative decarboxylation of isocitrate to α-KG, and facilitates the conversion of α-KG to 2-HG. IDH1/2 mutations confer an enzymatic gain of function that dramatically increases 2-HG in AML. This provides an explanation for the heterozygous acquisition of these mutations during tumorigenesis. 2-HG is a tractable metabolic biomarker of mutant IDH1/2 enzyme activity.

Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms

“…4 However, recent studies showed that impaired platelet production also contributes to the pathogenesis of ITP. 5 Consistent with these findings, two second-line thrombopoietin receptor (TPO-R) agonists, romiplostim (Nplate, Amgen, Thousand Oaks, CA, USA) and eltrombopag (Promacta, GlaxoSmithKline, Research Triangle Park, NC USA), 6 showed remarkable efficacy in patients with primary ITP. 7,8 As these trials excluded patients with secondary ITP, the activity of these new drugs in CLL-associated ITP has not been reported.…”

“…6,7 Arginine substitutions in both IDH1 and IDH2 are likely gain-of-function mutations that would result in the accumulation of 2-hydroxyglutarate. 6 We identified one case of refractory anemia with ringed sideroblast and thrombocytosis harboring a JAK2 V617F mutation together with an IDH2 R140L substitution. IDH2 mutations have been shown to be acquired during the evolution of two cases of JAK2 V617F-positive MPN to AML.…”

AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations

“…Recurrent somatic point mutations in active site arginine residues of IDH1 (R132) and IDH2 (R140 and R172) have been found in multiple tumors, including acute myeloid leukemia (AML; refs. [3][4][5][6][7][8][9]. Cancer-associated IDH1/2 mutations confer the neomorphic activity of reducing αKG to the oncometabolite (R)-2-hydroxyglutarate (2HG; refs.…”

The prognostic impact and stability of Isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia

“…10,11 The IDH mutants gain the neomorphic enzyme activity and lead to the production of an onco-metabolite, 2-hydroxyglutarate (2-HG), which was speculated to upregulate hypoxia-inducing factor 1a by inhibition of prolyl hydroxylase. 1,2,10,12 On the basis of the in vivo functions of IDH1 and IDH2, it is intuitive to expect similar clinical and biological characteristics between AML bearing mutations of these two genes. Indeed, mutations of both genes are more commonly present in patients with normal cytogenetics.…”