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

4 years ago

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

Duchosal, Clavio, Colombo, Cagnetta, Gobbi, Soncini, Talarico, Bruzzone, Guolo, Passalacqua, Cea, Minetto, Lemoli, Orecchioni, Retali, Nencioni, Bertolini, Nahimana, Todoerti, Carminati, Neri, Miglino, Bergamaschi

Genomic instability plays a pathological role in various malignancies, including acute myeloid leukemia, and thus represents 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 Acute Myeloid Leukemia 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 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 DNA-repair mechanisms disruption, genomic instability and aggressive Acute Myeloid Leukemia. This synthetic lethal approach, enhancing DNA damage while concomitantly blocking repair responses, provides the rationale for the clinical evaluation of SIRT6 modulators in leukemia treatment.

Publisher URL: http://doi.org/10.3324/haematol.2017.176248

DOI: 10.3324/haematol.2017.176248