Blood Journal
Leading the way in experimental and clinical research in hematology

SIRT1 prevents genotoxic stress-induced p53 activation in acute myeloid leukemia

  1. Daniel Sasca1,
  2. Patricia S. Hähnel1,
  3. Jakub Szybinski1,
  4. Kaml Khawaja1,
  5. Oliver Kriege1,
  6. Saskia V. Pante1,
  7. Lars Bullinger2,
  8. Susanne Strand3,
  9. Dennis Strand3,
  10. Matthias Theobald1, and
  11. Thomas Kindler1
  1. 1Third Department of Medicine, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany;
  2. 2Department of Internal Medicine III, University of Ulm, Germany; and
  3. 3First Department of Internal Medicine, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany

Key Points

  • SIRT1 is highly expressed in subsets of patients with acute myeloid leukemia harboring activating mutations in signaling pathways and is regulated at the protein levels.

  • Targeting SIRT1 sensitizes leukemic blast to tyrosine kinase inhibitor treatment or chemotherapy via restoration of p53 activity.

Abstract

SIRT1 is an important regulator of cellular stress response and genomic integrity. Its role in tumorigenesis is controversial. Whereas sirtuin 1 (SIRT1) can act as a tumor suppressor in some solid tumors, increased expression has been demonstrated in many cancers, including hematologic malignancies. In chronic myeloid leukemia, SIRT1 promoted leukemia development, and targeting SIRT1 sensitized chronic myeloid leukemia progenitors to tyrosine kinase inhibitor treatment. In this study, we investigated the role of SIRT1 in acute myeloid leukemia (AML). We show that SIRT1 protein, but not RNA levels, is overexpressed in AML samples harboring activating mutations in signaling pathways. In FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)+-cells protein, expression of SIRT1 is regulated by FLT3 kinase activity. In addition, SIRT1 function is modulated via the ATM-DBC1-SIRT1 axis in a FLT3-ITD-dependent manner. In murine leukemia models driven by MLL-AF9 or AML1-ETO coexpressing FLT3-ITD, SIRT1 acts as a safeguard to counteract oncogene-induced stress, and leukemic blasts become dependent on SIRT1 activity. Pharmacologic targeting or RNAi-mediated knockdown of SIRT1 inhibited cell growth and sensitized AML cells to tyrosine kinase inhibitor treatment and chemotherapy. This effect was a result of the restoration of p53 activity. Our data suggest that targeting SIRT1 represents an attractive therapeutic strategy to overcome primary resistance in defined subsets of patients with AML.

  • Submitted November 18, 2013.
  • Accepted May 7, 2014.
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