Depletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells' vulnerability to DNA-damaging agents.

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Version: Final published version
License: CC BY-NC 4.0
Serval ID
serval:BIB_0A0458D4A8E8
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Depletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells' vulnerability to DNA-damaging agents.
Journal
Haematologica
Author(s)
Cagnetta A., Soncini D., Orecchioni S., Talarico G., Minetto P., Guolo F., Retali V., Colombo N., Carminati E., Clavio M., Miglino M., Bergamaschi M., Nahimana A., Duchosal M., Todoerti K., Neri A., Passalacqua M., Bruzzone S., Nencioni A., Bertolini F., Gobbi M., Lemoli R.M., Cea M.
ISSN
1592-8721 (Electronic)
ISSN-L
0390-6078
Publication state
Published
Issued date
01/2018
Peer-reviewed
Oui
Volume
103
Number
1
Pages
80-90
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Genomic instability plays a pathological role in various malignancies, including acute myeloid leukemia (AML), and thus represents a potential therapeutic target. Recent studies demonstrate that SIRT6, a NAD <sup>+</sup> -dependent nuclear deacetylase, functions as genome-guardian by preserving DNA integrity in different tumor cells. Here, we demonstrate that also CD34 <sup>+</sup> blasts from AML patients show ongoing DNA damage and SIRT6 overexpression. Indeed, we identified a poor-prognostic subset of patients, with widespread instability, which relies on SIRT6 to compensate for DNA-replication stress. As a result, SIRT6 depletion compromises the ability of leukemia cells to repair DNA double-strand breaks that, in turn, increases their sensitivity to daunorubicin and Ara-C, both in vitro and in vivo In contrast, low SIRT6 levels observed in normal CD34 <sup>+</sup> hematopoietic progenitors explain their weaker sensitivity to genotoxic stress. Intriguingly, we have identified DNA-PKcs and CtIP deacetylation as crucial for SIRT6-mediated DNA repair. Together, our data suggest that inactivation of SIRT6 in leukemia cells leads to disruption of DNA-repair mechanisms, genomic instability and aggressive AML. This synthetic lethal approach, enhancing DNA damage while concomitantly blocking repair responses, provides the rationale for the clinical evaluation of SIRT6 modulators in the treatment of leukemia.
Keywords
Animals, Antineoplastic Agents/pharmacology, Ataxia Telangiectasia Mutated Proteins/metabolism, Biomarkers, Tumor, Cell Line, Tumor, Cell Proliferation/drug effects, Checkpoint Kinase 2/metabolism, DNA Damage/drug effects, DNA Repair, Disease Models, Animal, Enzyme Activation, Gene Expression, Genomic Instability, Humans, Immunophenotyping, Leukemia, Myeloid, Acute/genetics, Leukemia, Myeloid, Acute/metabolism, Leukemia, Myeloid, Acute/mortality, Leukemia, Myeloid, Acute/pathology, Mice, Neoplastic Stem Cells/metabolism, Neoplastic Stem Cells/pathology, Prognosis, Protein Binding, Sirtuins/genetics, Sirtuins/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
30/10/2017 9:40
Last modification date
20/08/2019 13:32
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