Combination targeted therapy to disrupt aberrant oncogenic signaling and reverse epigenetic dysfunction in IDH2- and TET2-mutant acute myeloid leukemia Journal Article


Authors: Shih, A. H.; Meydan, C.; Shank, K.; Garrett-Bakelman, F. E.; Ward, P. S.; Intlekofer, A. M.; Nazir, A.; Stein, E. M.; Knapp, K.; Glass, J.; Travins, J.; Straley, K.; Gliser, C.; Mason, C. E.; Yen, K.; Thompson, C. B.; Melnick, A.; Levine, R. L.
Article Title: Combination targeted therapy to disrupt aberrant oncogenic signaling and reverse epigenetic dysfunction in IDH2- and TET2-mutant acute myeloid leukemia
Abstract: Genomic studies in acute myeloid leukemias (AML) have identified mutations that drive altered DNA methylation, including TET2 and IDH2. Here, we show that models of AML resulting from TET2 or IDH2 mutations combined with FLT3ITD mutations are sensitive to 5-azacytidine or to the IDH2 inhibitor AG-221, respectively. 5-azacytidine and AG-221 treatment induced an attenuation of aberrant DNA methylation and transcriptional output and resulted in a reduction in leukemic blasts consistent with antileukemic activity. These therapeutic benefits were associated with restoration of leukemic cell differentiation, and the normalization of hematopoiesis was derived from mutant cells. By contrast, combining AG-221 or 5-azacytidine with FLT3 inhibition resulted in a reduction in mutant allele burden, progressive recovery of normal hematopoiesis from non-mutant stemprogenitor cells, and reversal of dysregulated DNA methylation and transcriptional output. Together, our studies suggest combined targeting of signaling and epigenetic pathways can increase therapeutic response in AML. © 2017 American Association for Cancer Research.
Journal Title: Cancer Discovery
Volume: 7
Issue: 5
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2017-05-01
Start Page: 494
End Page: 505
Language: English
DOI: 10.1158/2159-8290.cd-16-1049
PROVIDER: scopus
PMCID: PMC5413413
PUBMED: 28193779
DOI/URL:
Notes: Article -- Export Date: 2 June 2017 -- Source: Scopus
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MSK Authors
  1. Eytan Moshe Stein
    346 Stein
  2. Alan H Shih
    59 Shih
  3. Ross Levine
    778 Levine
  4. Patrick Shea Ward
    16 Ward
  5. Kristina M Knapp
    33 Knapp
  6. Craig Bernie Thompson
    153 Thompson
  7. Kaitlyn Ruth Shank
    20 Shank
  8. Jacob Lowell Glass
    56 Glass
  9. Abbas Nazir
    9 Nazir