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Ann Hematol. 2017 Dec;96(12):1983-1991. doi: 10.1007/s00277-017-3161-0. Epub 2017 Oct 31.

The role of mutant IDH1 and IDH2 inhibitors in the treatment of acute myeloid leukemia.

Author information

1
The George Washington University School of Medicine, Washington, DC, USA.
2
The George Washington Cancer Center, Washington, DC, USA.
3
The George Washington University School of Medicine, Washington, DC, USA. itabbara@mfa.gwu.edu.
4
The George Washington Cancer Center, Washington, DC, USA. itabbara@mfa.gwu.edu.
5
Division of Hematology/Oncology and GW Cancer Center, George Washington University Medical Faculty Associates, 2150 Pennsylvania Avenue, NW, Washington, DC, 20037, USA. itabbara@mfa.gwu.edu.

Abstract

For decades, researchers have looked into the pathophysiology of acute myeloid leukemia (AML). With the advances in molecular techniques, the two-hit hypothesis was replaced by a multi-hit model, which also emphasizes the importance of aberrant epigenetic regulation in the pathogenesis of AML. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert α-ketoglutarate (αKG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple αKG-dependent dioxygenases. Inhibition of various classes of αKG-dependent dioxygenases results in dramatic epigenetic changes in hematopoietic cells, which has been found to directly impair differentiation. In addition to a global dysregulation of gene expression, other mechanisms have been described through which R2-HG promotes leukemic transformation including the induction of B cell lymphoma 2 dependency and stimulation of the EglN family of prolyl 4-hydroxylases (EglN). Due to the fact that mutations in IDH1 and IDH2 are acquired early during AML clonal evolution as well as because these mutations tend to remain stable during AML progression, the pharmaceutical industry has prompted the development of specific mutant IDH enzyme inhibitors. More recently, the FDA approved the first mutant IDH2 inhibitor, enasidenib (AG-221), for patients with relapsed or refractory IDH2-mutated AML (RR-AML). This has brought a lot of excitement to researchers, clinicians, and patients, especially because the treatment of AML remains challenging and is still associated with a high mortality.

KEYWORDS:

AML; Clinical trial; Enasidenib; IDH; Leukemogenesis

PMID:
29090344
DOI:
10.1007/s00277-017-3161-0
[Indexed for MEDLINE]

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