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

Nature Communications
Thomas OellerichJindrich Cinatl

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.

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Citations

Jun 26, 2020·Communications Biology·Tamara RothenburgerJindrich Cinatl
Nov 26, 2020·Molecular & Cellular Oncology·Tamara Davenne, Jan Rehwinkel
Jun 21, 2020·Developmental Biology·Siba Shanak, Volkhard Helms
Sep 5, 2021·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Kerstin SchottRenate König
Oct 14, 2021·Journal of Experimental & Clinical Cancer Research : CR·Tamara RothenburgerJindrich Cinatl

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Methods Mentioned

BETA
PCR
xenografts
flow cytometry
MDS
size-exclusion chromatography
transfection
electrophoresis
biopsy
biopsies
light microscopy

Software Mentioned

FlowJo
TreeStar
PHASER
7500 System
R
Refmac
Coot
drm

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