Open AccessDepletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells’ vulnerability to DNA-damaging agents
Author(s) -
Antonia Cagnetta,
Debora Soncini,
Stefania Orecchioni,
Giovanna Talarico,
Paola Minetto,
Fabio Guolo,
Veronica Retali,
Nicoletta Colombo,
Enrico Carminati,
Marino Clavio,
Maurizio Miglino,
Micaela Bergamaschi,
Aimable Nahimana,
Michael Duchosal,
Katia Todoerti,
Antonino Neri,
Mario Passalacqua,
Santina Bruzzone,
Alessio Nencioni,
Francesco Bertolini,
Marco Gobbi,
Roberto M. Lemoli,
Michele Cea
Publication year - 2017
Publication title -
haematologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.782
H-Index - 142
eISSN - 1592-8721
pISSN - 0390-6078
DOI - 10.3324/haematol.2017.176248
Subject(s) - genome instability , myeloid leukemia , dna repair , dna damage , cancer research , daunorubicin , biology , haematopoiesis , leukemia , dna , stem cell , microbiology and biotechnology , genetics
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.