Abstract
Approximately 20% of unselected cases and 30% cytogenetically diploid cases of acute myeloid leukemia (AML) and 80% of grade II–III gliomas and secondary glioblastomas carry mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. IDH1/2 mutations prevent oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) and modulate the function of IDH (neomorphic activity) thereby facilitating reduction of α-KG to D-2-hydroxyglutarate (D-2HG), a putative oncometabolite. D-2HG is thought to act as a competitive inhibitor of α-KG-dependent dioxygenases that include prolyl hydroxylases and chromatin-modifying enzymes. The end result is a global increase of cellular DNA hypermethylation and alterations of the cellular epigenetic state, which has been proposed to play a role in the development of a variety of tumors. In this review, we provide an update on potential molecular mechanisms linking IDH1/2 mutations and the resulting oncometabolite, D-2HG, with malignant transformation. In addition, in patients with AML and glioma we focus on the associations between IDH1/2 mutations and clinical, morphologic, cytogenetic, and molecular characteristics.
Highlights
There is increasing evidence that alterations in cellular metabolism are involved in the pathogenesis of many cancers
PERSPECTIVES IDH1R132, IDH2R140, and IDH2R172 mutations represent a novel class of point mutations in patients with acute myeloid leukemia (AML) and glioma
In AML patients, it is possible that IDH1R132, IDH2R140, and IDH2R172 mutations represent molecular or clinically distinctive subgroups, with IDH1R132 and IDH2R140 more frequently accompanied by normal cytogenetics and NPM1 mutation, whereas IDH2R172 is frequently the only mutation detected and portends a poor prognosis
Summary
There is increasing evidence that alterations in cellular metabolism are involved in the pathogenesis of many cancers. Subsequent analyzes on a large number of AML patients treated on multiple clinical protocols confirmed the presence of IDH1R132 mutations and identified IDH2R140 and IDH2R172 mutations in ∼20% of adult-onset AML with normal cytogenetics (Mardis et al, 2009; Abbas et al, 2010; Boissel et al, 2010; Green et al, 2010; Gross et al, 2010; Ho et al, 2010; Marcucci et al, 2010; Paschka et al, 2010; Schnittger et al, 2010; Thol et al, 2010a). Others have suggested that overproduction of d-2HG promotes oncogenesis (Koivunen et al, 2012; Losman et al, 2013) and IDH1 and IDH2 mutations are likely the integrally involved in the pathogenesis of malignant transformation (i.e., driver mutations) rather than epiphenomena
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