Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML

Nat Commun. 2019 Aug 2;10(1):3475. doi: 10.1038/s41467-019-11413-4.

Abstract

Hypomethylating agents decitabine and azacytidine are regarded as interchangeable in the treatment of acute myeloid leukemia (AML). However, their mechanisms of action remain incompletely understood, and predictive biomarkers for HMA efficacy are lacking. Here, we show that the bioactive metabolite decitabine triphosphate, but not azacytidine triphosphate, functions as activator and substrate of the triphosphohydrolase SAMHD1 and is subject to SAMHD1-mediated inactivation. Retrospective immunohistochemical analysis of bone marrow specimens from AML patients at diagnosis revealed that SAMHD1 expression in leukemic cells inversely correlates with clinical response to decitabine, but not to azacytidine. SAMHD1 ablation increases the antileukemic activity of decitabine in AML cell lines, primary leukemic blasts, and xenograft models. AML cells acquire resistance to decitabine partly by SAMHD1 up-regulation. Together, our data suggest that SAMHD1 is a biomarker for the stratified use of hypomethylating agents in AML patients and a potential target for the treatment of decitabine-resistant leukemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / pharmacology*
  • Antimetabolites, Antineoplastic / therapeutic use
  • Azacitidine / analogs & derivatives
  • Azacitidine / pharmacology
  • Azacitidine / therapeutic use
  • Biomarkers, Tumor / metabolism*
  • Bone Marrow / pathology
  • Cell Line, Tumor
  • DNA Methylation / drug effects
  • Decitabine / pharmacology
  • Decitabine / therapeutic use
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Gene Expression Regulation, Leukemic / drug effects
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Patient Selection
  • Primary Cell Culture
  • Retrospective Studies
  • SAM Domain and HD Domain-Containing Protein 1 / metabolism*
  • Treatment Outcome
  • Xenograft Model Antitumor Assays

Substances

  • Antimetabolites, Antineoplastic
  • Biomarkers, Tumor
  • guadecitabine
  • Decitabine
  • SAM Domain and HD Domain-Containing Protein 1
  • SAMHD1 protein, human
  • Azacitidine