SAMHD1 Is a Biomarker for Cytarabine Response and a Therapeutic Target in Acute Myeloid Leukemia

Nat Med. 2017 Feb;23(2):250-255. doi: 10.1038/nm.4255. Epub 2016 Dec 19.

Abstract

The nucleoside analog cytarabine (Ara-C) is an essential component of primary and salvage chemotherapy regimens for acute myeloid leukemia (AML). After cellular uptake, Ara-C is converted into its therapeutically active triphosphate metabolite, Ara-CTP, which exerts antileukemic effects, primarily by inhibiting DNA synthesis in proliferating cells. Currently, a substantial fraction of patients with AML fail to respond effectively to Ara-C therapy, and reliable biomarkers for predicting the therapeutic response to Ara-C are lacking. SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate. Although it has been postulated that SAMHD1 sensitizes cancer cells to nucleoside-analog derivatives through the depletion of competing dNTPs, we show here that SAMHD1 reduces Ara-C cytotoxicity in AML cells. Mechanistically, dGTP-activated SAMHD1 hydrolyzes Ara-CTP, which results in a drastic reduction of Ara-CTP in leukemic cells. Loss of SAMHD1 activity-through genetic depletion, mutational inactivation of its triphosphohydrolase activity or proteasomal degradation using specialized, virus-like particles-potentiates the cytotoxicity of Ara-C in AML cells. In mouse models of retroviral AML transplantation, as well as in retrospective analyses of adult patients with AML, the response to Ara-C-containing therapy was inversely correlated with SAMHD1 expression. These results identify SAMHD1 as a potential biomarker for the stratification of patients with AML who might best respond to Ara-C-based therapy and as a target for treating Ara-C-refractory AML.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Antimetabolites, Antineoplastic / pharmacology
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cytarabine / administration & dosage
  • Cytarabine / pharmacology
  • Cytarabine / therapeutic use*
  • Daunorubicin / administration & dosage
  • Disease Models, Animal
  • Female
  • Flow Cytometry
  • Humans
  • Immunoblotting
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / metabolism
  • Male
  • Middle Aged
  • Monomeric GTP-Binding Proteins / metabolism*
  • Prognosis
  • Retrospective Studies
  • SAM Domain and HD Domain-Containing Protein 1
  • Young Adult

Substances

  • Antimetabolites, Antineoplastic
  • Cytarabine
  • SAM Domain and HD Domain-Containing Protein 1
  • SAMHD1 protein, human
  • Samhd1 protein, mouse
  • Monomeric GTP-Binding Proteins
  • Daunorubicin