ISSN 2997-1036
International Journal of Hematology | Vol. 10, No. 5, May 2019 | pp. 33–40
DOI: 10.46882/2019/IJH/000113
Review Article
Title: Structural biology and targeted biochemical inhibition of IDH1 and IDH2 mutations in acute myeloid leukemia cells
Names of Authors: M. A. Bello¹, O. R. Eze²
Authors’ Affiliations: ¹Department of Haematology, Aminu Kano Teaching Hospital, Kano, Nigeria; ²Department of Pathology, University of Benin, Benin City, Nigeria
Abstract: Somatic mutations within the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes create neomorphic enzymatic activities that alter cellular differentiation pathways in acute myeloid leukemia. This comprehensive review synthesizes current insights into the structural structural biology of these variants, highlighting how point mutations at key arginine residues (IDH1 R132, IDH2 R140/R172) drive the abnormal reduction of alpha-ketoglutarate into the oncometabolite 2-hydroxyglutarate (2-HG). The accumulation of 2-hydroxyglutarate competitively inhibits alpha-ketoglutarate-dependent dioxygenases, driving widespread DNA hypermethylation and blocking myeloid progenitor maturation. Evolving management models highlight small-molecule targeted inhibitors, including ivosidenib (AG-120) for IDH1 and enasidenib (AG-221) for IDH2. These agents bind to the allosteric pockets of mutant dimers, suppressing oncometabolite production and releasing the differentiation block without inducing cytotoxic marrow aplasia. However, treatment can precipitate differentiation syndrome, requiring swift corticosteroid protocols. This review outlines clear biomarker tracking systems, 2-hydroxyglutarate clearance monitoring, and combination schedules designed to bypass resistance and optimize outcomes in IDH-mutated myeloid leukemias.
Keywords: Acute myeloid leukemia, IDH1 mutation, IDH2 mutation, 2-hydroxyglutarate, differentiation therapy
Manuscript Timeline: Received: February 12, 2019; Revised: March 22, 2019; Accepted: April 10, 2019; Published: May 18, 2019