IDH1 and IDH2 Mutations Are Frequent Genetic Alterations in Acute Myeloid Leukemia and Confer Adverse Prognosis in Cytogenetically Normal Acute Myeloid Leukemia With NPM1 Mutation Without FLT3 Internal Tandem Duplication

Abstract

IDH1 and IDH2 mutations are recurring genetic changes in AML. They constitute a poor prognostic factor in CN-AML with mutated NPM1 without FLT3-ITD, which allows refined risk stratification of this AML subset.

DNMT3A mutations in acute myeloid leukemia

“…Mutations in NPM1, IDH1, and IDH2 were not detected in these patients either, a finding that is consistent with data reported in other studies. 4,[27][28][29][30] The virtual exclusion of mutations in these four genes in patients with a favorable-risk profile is not random and may reflect the leukemogenic properties of the fusion proteins created by these chromosomal rearrangements. The PML-RARA fusion protein, which is created by t(15;17), physically interacts with DNMT3A, and AML-ETO, which is created by t(8;21), interacts with DNMT1; both fusion proteins alter the methylation of specific promoters.…”

Concise Review: The Role of Hematopoietic Stem Cell Transplantation in the Treatment of Acute Myeloid Leukemia

“…Somatic mutations of isocitrate dehydrogenase enzyme isoform 1 (IDH1) and isoform 2 (IDH2) [30] and the DNA methyltransferase gene DNMT3A [31] in CN-AML have been associated with adverse outcomes depending on their association with other mutations. The validation and identification by deep sequencing of hundreds of somatic mutations in AML [8] suggest that better genetic definition will further refine selection of patients for HSCT.…”

Targeting MTHFD2 in acute myeloid leukemia

“…Mutations in genes of the succinate dehydrogenase complex, critical for both the tricarboxylic acid (TCA) cycle and electron transport chain, have been implicated in the pathogenesis of hereditary paragangliomas (Baysal et al, 2000;Niemann and Müller, 2000), pheochromocytomas (Astuti et al, 2001), renal cell cancer (Vanharanta et al, 2004), and gastrointestinal stromal tumors (Janeway et al, 2011;Pantaleo et al, 2011). In addition, mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) have been found in subsets of gliomas (Yan et al, 2009;Brennan et al, 2013) and acute myeloid leukemia (AML; Paschka et al, 2010;Cancer Genome Atlas Research Network, 2013), among other malignancies. Drugs targeting these mutant proteins have entered the clinic with some successes in early phase trials (Stein et al 2014.…”