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Haematologica. 2018 Jan;103(1):80-90. doi: 10.3324/haematol.2017.176248. Epub 2017 Oct 12.

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

Author information

1
Chair of Hematology, Department of Internal Medicine (DiMI), University of Genova, Italy.
2
Hematology Unit, Policlinico San Martino, Genova, Italy.
3
European Institute of Oncology, Milan, Italy.
4
Service and Central Laboratory of Hematology, University Hospital of Lausanne, Switzerland.
5
Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture, Potenza, Italy.
6
Department of Oncology and Hemato-Oncology, University of Milan, Italy.
7
Hematology Unit, Fondazione Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy.
8
Department of Experimental Medicine, University of Genova, Italy and.
9
Department of Internal Medicine, University of Genova, Italy.
10
Chair of Hematology, Department of Internal Medicine (DiMI), University of Genova, Italy michele.cea@unige.it.

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+-dependent nuclear deacetylase, functions as genome-guardian by preserving DNA integrity in different tumor cells. Here, we demonstrate that also CD34+ 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+ 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.

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PMID:
29025907
PMCID:
PMC5777193
DOI:
10.3324/haematol.2017.176248
[Indexed for MEDLINE]
Free PMC Article

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