title: SIRT1 prevents genotoxic stress-induced p53 activation in acute myeloid leukemia.
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.
authors.affiliation: Third Department of Medicine, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany;
authors.forename: Daniel
authors.initials: D
authors.lastname: Sasca
authors.affiliation: Third Department of Medicine, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany;
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Hähnel
authors.affiliation: Third Department of Medicine, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany;
authors.forename: Jakub
authors.initials: J
authors.lastname: Szybinski
authors.affiliation: Third Department of Medicine, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany;
authors.forename: Kaml
authors.initials: K
authors.lastname: Khawaja
authors.affiliation: Third Department of Medicine, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany;
authors.forename: Oliver
authors.initials: O
authors.lastname: Kriege
authors.affiliation: Third Department of Medicine, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany;
authors.forename: Saskia V
authors.initials: SV
authors.lastname: Pante
authors.affiliation: Department of Internal Medicine III, University of Ulm, Germany; and.
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.affiliation: First Department of Internal Medicine, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Strand
authors.affiliation: First Department of Internal Medicine, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Strand
authors.affiliation: Third Department of Medicine, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany;
authors.forename: Matthias
authors.initials: M
authors.lastname: Theobald
authors.affiliation: Third Department of Medicine, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany;
authors.forename: Thomas
authors.initials: T
authors.lastname: Kindler
mesh_terms: D000818:Animals; D004249:DNA Damage / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D055879:Gene Knock-In Techniques; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000502:physiology; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; C447939:SIRT1 protein, human; D056564:Sirtuin 1