Format

Send to:

Choose Destination
See comment in PubMed Commons below
Cell Stem Cell. 2014 Oct 2;15(4):431-46. doi: 10.1016/j.stem.2014.08.001.

SIRT1 activation by a c-MYC oncogenic network promotes the maintenance and drug resistance of human FLT3-ITD acute myeloid leukemia stem cells.

Author information

  • 1Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA 91010, USA.
  • 2Department of Clinical Science, Hematology Section, University of Bergen, Bergen 5021, Norway.
  • 3Department of Cancer Biology, City of Hope National Medical Center, Duarte, CA 91010, USA.
  • 4KinN Therapeutics AS, Bergen 5008, Norway.
  • 5Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen 5021, Norway.
  • 6Department of Clinical Science, Hematology Section, University of Bergen, Bergen 5021, Norway; Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen 5021, Norway.
  • 7Karolinska Institutet, Stockholm 17177, Sweden.
  • 8Department of Clinical Science, Hematology Section, University of Bergen, Bergen 5021, Norway; Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen 5021, Norway. Electronic address: emmet.mc.cormack@k2.uib.no.
  • 9Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA 91010, USA. Electronic address: rbhatia@coh.org.

Abstract

The FLT3-ITD mutation is frequently observed in acute myeloid leukemia (AML) and is associated with poor prognosis. In such patients, FLT3 tyrosine kinase inhibitors (TKIs) are only partially effective and do not eliminate the leukemia stem cells (LSCs) that are assumed to be the source of treatment failure. Here, we show that the NAD-dependent SIRT1 deacetylase is selectively overexpressed in primary human FLT3-ITD AML LSCs. This SIRT1 overexpression is related to enhanced expression of the USP22 deubiquitinase induced by c-MYC, leading to reduced SIRT1 ubiquitination and enhanced stability. Inhibition of SIRT1 expression or activity reduced the growth of FLT3-ITD AML LSCs and significantly enhanced TKI-mediated killing of the cells. Therefore, these results identify a c-MYC-related network that enhances SIRT1 protein expression in human FLT3-ITD AML LSCs and contributes to their maintenance. Inhibition of this oncogenic network could be an attractive approach for targeting FLT3-ITD AML LSCs to improve treatment outcomes.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
25280219
[PubMed - indexed for MEDLINE]
PMCID:
PMC4305398
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Write to the Help Desk