Isocitrate dehydrogenase 2 (NADP+), mitochondrial (IDH2) is a gene that encodes an epigenetic modifier, a NADP(+)-dependent enzyme that is found
in mitochondria (Gene
2013). Wild type IDH2 converts isocitrate to α-ketoglutarate, a step in the
Krebs cycle, an important metabolic pathway that affects many other cellular biochemical
processes (Shih et al.
IDH2 is frequently mutated in glioma, acute myeloid leukemia, and myelodysplastic
et al. 2014; Walter
et al. 2013; Yang
et al. 2012). Mutations generally
involve point mutations at the R140 and
R172 residues of the protein. Mutations in IDH1 and IDH2 result in
deleterious “gain of function”: instead of converting isocitrate to α-ketoglutarate,
mutated IDH1 or IDH2 converts isocitrate to 2-hydroxyglutarate (Shih et al.
2012; Yang et
al. 2012). 2-hydroxyglutarate inhibits other proteins involved in epigenetic
regulation (Shih et
Suggested Citation: Wheeler, S., A. Seegmiller, C. Vnencak-Jones, S. Clark, A.
Kim. 2015. IDH2. My Cancer Genome https://www.padiracinnovation.org/content/disease/acute-myeloid-leukemia/idh2/?tab=0
(Updated December 4).
Last Updated: December 4, 2015
IDH2 in Acute Myeloid Leukemia
IDH2 is mutated in 9.1% of acute
myeloid leukemia cases (COSMIC). Mutations
of the R140 or R172 residues both result in a protein
with different function; the new function is believed to contribute to leukemogenesis by
inhibiting normal epigenetic regulation (Feng et al. 2012;
Green et al. 2011; Jeziskova et al.
2010; Shih et al.
2012; Zhou et al. 2012). IDH2
mutations fall outside the “two-hit” theory of leukemogenesis as it was originally
conceived. Some have proposed categorizing IDH2 mutations into a new class of mutations; members
of the new class—class III—would be defined as mutations occurring in epigenetic
modifiers (Naoe and Kiyoi
2013; Shih et al.
2012). Similar to DNMT3A and IDH1 mutations, IDH2 mutations affect DNA methylation and
as such, play a role in cancer development through deregulation of gene expression.
Suggested Citation: Wheeler, S., A. Seegmiller, C. Vnencak-Jones. 2013. IDH2 in
Acute Myeloid Leukemia. My Cancer Genome https://www.padiracinnovation.org/content/disease/acute-myeloid-leukemia/idh2/
(Updated October 1).
Last Updated: October 1, 2013
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