Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition Journal Article


Authors: Chen, C.; Liu, Y.; Lu, C.; Cross, J. R.; Morris, J. P. 4th; Shroff, A. S.; Ward, P. S.; Bradner, J. E.; Thompson, C.; Lowe, S. W.
Article Title: Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition
Abstract: Somatic mutations in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 occur frequently in acute myeloid leukemia (AML) and other cancers. These genes encode neomorphic proteins that produce the presumed oncometabolite 2-hydroxyglutarate (2-HG). Despite the prospect of treating AML and other cancers by targeting IDH mutant proteins, it remains unclear how these mutants affect tumor development and maintenance in vivo, and no cancer models exist to study the action of IDH2 mutants in vivo. We show that IDH2 mutants can cooperate with oncogenic Flt3 or Nras alleles to drive leukemia in mice by impairing the differentiation of cells of the myeloid lineage. Pharmacologic or genetic inhibition of IDH2 triggers the differentiation and death of AML cells, albeit only with prolonged IDH2 inhibition. In contrast, inhibition of the bromodomain-containing protein Brd4 triggers rapid differentiation and death of IDH2 mutant AML. Our results establish a critical role for mutant IDH2 in leukemogenesis and tumor maintenance and identify an IDH-independent strategy to target these cancers therapeutically. © 2013, Published by Cold Spring Harbor Laboratory Press.
Keywords: controlled study; unclassified drug; oncoprotein; acute granulocytic leukemia; somatic mutation; nonhuman; mutant protein; protein domain; animal cell; mouse; allele; animal tissue; cell death; cancer susceptibility; enzyme inhibition; protein protein interaction; animal experiment; animal model; cell differentiation; cell lineage; genetic susceptibility; leukemia cell; leukemogenesis; targeted therapy; bone marrow cell; aml; oncogene n ras; cd135 antigen; tumor maintenance; isocitrate dehydrogenase 2; brd4 inhibition; idh mutants; brd4 protein
Journal Title: Genes and Development
Volume: 27
Issue: 18
ISSN: 0890-9369
Publisher: Cold Spring Harbor Laboratory Press  
Date Published: 2013-09-15
Start Page: 1974
End Page: 1985
Language: English
DOI: 10.1101/gad.226613.113
PROVIDER: scopus
PMCID: PMC3792474
PUBMED: 24065765
DOI/URL:
Notes: --- - "Export Date: 1 November 2013" - "CODEN: GEDEE" - "Source: Scopus"
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MSK Authors
  1. Chao Lu
    19 Lu
  2. Patrick Shea Ward
    16 Ward
  3. Justin Robert Cross
    111 Cross
  4. Scott W Lowe
    249 Lowe
  5. Yu Liu
    3 Liu
  6. Aditya Shishir Shroff
    3 Shroff
  7. Craig Bernie Thompson
    153 Thompson
  8. Chong Chen
    11 Chen