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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Checkpoint Kinase 2
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK2 protein, human
  • SIRT6 protein, human
  • Sirtuins