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

A. Cagnetta, D. Soncini, S. Orecchioni, G. Talarico, P. Minetto, F. Guolo, V. Retali, N. Colombo, E. Carminati, M. Clavio, M. Miglino, M. Bergamaschi, A. Nahimana, M. Duchosal, K. Todoerti, A. Neri, M. Passalacqua, S. Bruzzone, A. Nencioni, F. BertoliniM. Gobbi, R.M. Lemoli, M. Cea

Research output: Contribution to journalArticle

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. © 2018 Ferrata Storti Foundation.
Original languageEnglish
Pages (from-to)80-90
Number of pages11
JournalHaematologica
Volume103
Issue number1
DOIs
Publication statusPublished - 2018

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Keywords

  • ATM protein
  • CD34 antigen
  • checkpoint kinase 2
  • daunorubicin
  • sirtuin 6
  • acute myeloid leukemia
  • acute myeloid leukemia cell line
  • Article
  • blast cell
  • cell disruption
  • cell isolation
  • cell proliferation
  • clinical outcome
  • deacetylation
  • DNA damage
  • DNA damage response
  • DNA repair
  • DNA replication
  • enzyme activity
  • flow cytometry
  • gene expression
  • gene knockdown
  • gene overexpression
  • genome
  • genomic instability
  • genotoxicity
  • hematopoietic cell
  • HL-60 cell line
  • human
  • immunofluorescence
  • immunoprecipitation
  • in vitro study
  • in vivo study
  • leukemia cell
  • nonhuman
  • pathogenesis
  • peripheral blood mononuclear cell
  • primary cell
  • prognosis
  • protein depletion
  • protein phosphorylation
  • receptor down regulation
  • staining
  • stem cell
  • tumor cell
  • tumor engraftment
  • tumor growth
  • U-937 cell line
  • Western blotting

Cite this

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., ... Cea, M. (2018). Depletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells’ vulnerability to DNA-damaging agents. Haematologica, 103(1), 80-90. https://doi.org/10.3324/haematol.2017.176248