PMID- 27721426
OWN - NLM
STAT- MEDLINE
DCOM- 20170901
LR  - 20181113
IS  - 1476-5551 (Electronic)
IS  - 0887-6924 (Linking)
VI  - 31
IP  - 2
DP  - 2017 Feb
TI  - Isocitrate dehydrogenase mutations in myeloid malignancies.
PG  - 272-281
LID - 10.1038/leu.2016.275 [doi]
AB  - Alterations to genes involved in cellular metabolism and epigenetic regulation
      are implicated in the pathogenesis of myeloid malignancies. Recurring mutations
      in isocitrate dehydrogenase (IDH) genes are detected in approximately 20% of
      adult patients with acute myeloid leukemia (AML) and 5% of adults with
      myelodysplastic syndromes (MDS). IDH proteins are homodimeric enzymes involved in
      diverse cellular processes, including adaptation to hypoxia, histone
      demethylation and DNA modification. The IDH2 protein is localized in the
      mitochondria and is a critical component of the tricarboxylic acid (also called
      the 'citric acid' or Krebs) cycle. Both IDH2 and IDH1 (localized in the
      cytoplasm) proteins catalyze the oxidative decarboxylation of isocitrate to
      alpha-ketoglutarate (alpha-KG). Mutant IDH enzymes have neomorphic activity and
      catalyze reduction of alpha-KG to the (R) enantiomer of 2-hydroxyglutarate, which
      is associated with DNA and histone hypermethylation, altered gene expression and 
      blocked differentiation of hematopoietic progenitor cells. The prognostic
      significance of mutant IDH (mIDH) is controversial but appears to be influenced
      by co-mutational status and the specific location of the mutation (IDH1-R132,
      IDH2-R140, IDH2-R172). Treatments specifically or indirectly targeted to mIDH are
      currently under clinical investigation; these therapies have been generally well 
      tolerated and, when used as single agents, have shown promise for inducing
      responses in some mIDH patients when used as first-line treatment or in relapsed 
      or refractory AML or MDS. Use of mIDH inhibitors in combination with drugs with
      non-overlapping mechanisms of action is especially promising, as such regimens
      may address the clonal heterogeneity and the multifactorial pathogenic processes 
      involved in mIDH myeloid malignancies. Advances in mutational analysis have made 
      testing more rapid and convenient, and less expensive; such testing should become
      part of routine diagnostic workup and repeated at relapse to identify patients
      who may benefit from treatments that target mIDH.
FAU - Medeiros, B C
AU  - Medeiros BC
AD  - Division of Hematology, Department of Medicine, Stanford University School of
      Medicine, Stanford Cancer Center, Stanford, CA, USA.
FAU - Fathi, A T
AU  - Fathi AT
AD  - Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA,
      USA.
FAU - DiNardo, C D
AU  - DiNardo CD
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center,
      Houston, TX, USA.
FAU - Pollyea, D A
AU  - Pollyea DA
AD  - Division of Hematology, University of Colorado School of Medicine, Aurora, CO,
      USA.
FAU - Chan, S M
AU  - Chan SM
AD  - Princess Margaret Cancer Centre, Toronto, ON, Canada.
FAU - Swords, R
AU  - Swords R
AD  - Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
LA  - eng
GR  - KL2 TR000461/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Review
DEP - 20161010
PL  - England
TA  - Leukemia
JT  - Leukemia
JID - 8704895
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Isoenzymes)
RN  - EC 1.1.1.41 (Isocitrate Dehydrogenase)
SB  - IM
MH  - Animals
MH  - Biomarkers, Tumor
MH  - DNA Mutational Analysis
MH  - Gene Frequency
MH  - Humans
MH  - Isocitrate Dehydrogenase/*genetics/metabolism
MH  - Isoenzymes
MH  - Leukemia, Myeloid, Acute/enzymology/epidemiology/*genetics/mortality
MH  - *Mutation
MH  - Myelodysplastic Syndromes/enzymology/epidemiology/genetics
MH  - Prognosis
PMC - PMC5292675
COIS- BCM has received research funding from Celgene and Agios and has received
      remuneration for Advisory Board participation from Celgene and Agios. ATF is a
      consultant for and receives clinical research funding from Celgene and declares
      Advisory Board participation for Agios. CDD has received research funding from
      Novartis, Celgene, Agios and Abbvie/Genentech and participates in Advisory Boards
      for Celgene and Agios. DAP has received research funding from Celgene and is a
      consultant for Celgene, Pfizer, Alexion, Ariad and Karyopharm. SMC has received
      research funding from Celgene, Agios and Abbvie/Genentech. RS declares Advisory
      Board participation for Novartis.
EDAT- 2016/10/11 06:00
MHDA- 2017/09/02 06:00
CRDT- 2016/10/11 06:00
PHST- 2016/06/28 00:00 [received]
PHST- 2016/08/17 00:00 [revised]
PHST- 2016/08/25 00:00 [accepted]
PHST- 2016/10/11 06:00 [pubmed]
PHST- 2017/09/02 06:00 [medline]
PHST- 2016/10/11 06:00 [entrez]
AID - leu2016275 [pii]
AID - 10.1038/leu.2016.275 [doi]
PST - ppublish
SO  - Leukemia. 2017 Feb;31(2):272-281. doi: 10.1038/leu.2016.275. Epub 2016 Oct 10.