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

Item Type:	Article
Title:	SIRT1 prevents genotoxic stress-induced p53 activation in acute myeloid leukemia
Creators Name:	Sasca, D. and Hähnel, P.S. and Szybinski, J. and Khawaja, K. and Kriege, O. and Pante, S.V. and Bullinger, L. and Strand, S. and Strand, D. and Theobald, M. and Kindler, T.
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.
Keywords:	Acute Myeloid Leukemia, DNA Damage, Enzyme Activation, Gene Knock-In Techniques, Gene Knockdown Techniques, Heterografts, Inbred C57BL Mice, Signal Transduction, Sirtuin 1, Tumor Suppressor Protein p53, Animals, Mice
Source:	Blood
ISSN:	0006-4971
Publisher:	American Society of Hematology
Volume:	124
Number:	1
Page Range:	121-133
Date:	3 July 2014
Official Publication:	https://doi.org/10.1182/blood-2013-11-538819
PubMed:	View item in PubMed

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