• What is IDH1?
  • IDH1 in Acute Myeloid Leukemia
  • IDH1 c.395G>T (R132L)
  • Clinical Trials

IDH1

Isocitrate dehydrogenase 1 (NADP+), soluble (IDH1) is a gene that encodes an epigenetic modifier, a NADP(+)-dependent enzyme that catalyzes oxidative decarboxylation of isocitrate (Gene 2013). Wild type IDH1 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. 2012).

IDH1 is frequently mutated in glioma and acute myeloid leukemia, myelodysplastic syndromes, and other cancer types (Rohle et al. 2013; Walter et al. 2013). Mutations generally involve point mutations at the R132 residue of the protein, although a synonymous variant (G105G) has been found to be prognostically relevant in AML. 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 al. 2012).

Related Pathways

Contributors: Scott Wheeler, Ph.D. (through June 2014), Adam Seegmiller, M.D., Ph.D., Cindy L. Vnencak-Jones, Ph.D., Stephen A. Strickland, M.D., MSCI, Annette S. Kim, M.D., Ph.D.

Suggested Citation: Wheeler, S., A. Seegmiller, C. Vnencak-Jones, S. Strickland, A. Kim. 2015. IDH1. My Cancer Genome https://www.padiracinnovation.org/content/disease/acute-myeloid-leukemia/idh1/?tab=0 (Updated December 4).

Last Updated: December 4, 2015

IDH1 in Acute Myeloid Leukemia

IDH1 is mutated in 6.4% of acute myeloid leukemia cases (COSMIC). Mutations of the R132 residue 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; Shih et al. 2012). IDH1 mutations fall outside the “two-hit” theory of leukemogenesis as it was originally conceived. Some have proposed categorizing IDH1 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 IDH2 mutations, IDH1 mutations affect DNA methylation and as such, play a role in cancer development through deregulation of gene expression.​

Contributors: Scott Wheeler, Ph.D. (through June 2014), Adam Seegmiller, M.D., Ph.D., Cindy L. Vnencak-Jones, Ph.D.

Suggested Citation: Wheeler, S., A. Seegmiller, C. Vnencak-Jones. 2013. IDH1 in Acute Myeloid Leukemia. My Cancer Genome https://www.padiracinnovation.org/content/disease/acute-myeloid-leukemia/idh1/ (Updated October 16).

Last Updated: October 16, 2013

IDH1 c.395G>T (R132L) Mutation in Acute Myeloid Leukemia

Properties
Location of mutation Exon 4 (Ensembl)
Frequency of IDH1 mutations in AML 6.4% (COSMIC)
Frequency of IDH1 R132L mutation in IDH1-mutated AML 5.0% (COSMIC)
Implications for Targeted Therapeutics
Response to FLT3 inhibitors Unknown at this time
Response to MEK inhibitors Unknown at this time
Response to JAK2 inhibitors Unknown at this time

The R132L mutation results in an amino acid substitution at position 132 in IDH1, from an arginine (R) to a leucine (L). The prognostic significance of this mutation is unclear (Dohner and Gaidzik 2011; Shih et al. 2012). In patients with normal karyotype and an NPM1 mutation, IDH1 mutations are associated with favorable prognosis in AML (Patel et al. 2012).​

Contributors: Scott Wheeler, Ph.D. (through June 2014), Adam Seegmiller, M.D., Ph.D., Cindy L. Vnencak-Jones, Ph.D.

Suggested Citation: Wheeler, S., A. Seegmiller, C. Vnencak-Jones. 2013. IDH1 c.395G>T (R132L) Mutation in Acute Myeloid Leukemia. My Cancer Genome https://www.padiracinnovation.org/content/disease/acute-myeloid-leukemia/idh1/264/ (Updated September 9).

Last Updated: September 9, 2013

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