Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML.
Animals
Antimetabolites, Antineoplastic
/ pharmacology
Azacitidine
/ analogs & derivatives
Biomarkers, Tumor
/ metabolism
Bone Marrow
/ pathology
Cell Line, Tumor
DNA Methylation
/ drug effects
Decitabine
/ pharmacology
Drug Resistance, Neoplasm
/ drug effects
Female
Gene Expression Regulation, Leukemic
/ drug effects
Humans
Leukemia, Myeloid, Acute
/ drug therapy
Mice
Patient Selection
Primary Cell Culture
Retrospective Studies
SAM Domain and HD Domain-Containing Protein 1
/ metabolism
Treatment Outcome
Xenograft Model Antitumor Assays
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
02 08 2019
02 08 2019
Historique:
received:
14
08
2018
accepted:
08
07
2019
entrez:
4
8
2019
pubmed:
4
8
2019
medline:
18
12
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31375673
doi: 10.1038/s41467-019-11413-4
pii: 10.1038/s41467-019-11413-4
pmc: PMC6677770
doi:
Substances chimiques
Antimetabolites, Antineoplastic
0
Biomarkers, Tumor
0
guadecitabine
2KT4YN1DP7
Decitabine
776B62CQ27
SAM Domain and HD Domain-Containing Protein 1
EC 3.1.5.-
SAMHD1 protein, human
EC 3.1.5.-
Azacitidine
M801H13NRU
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3475Subventions
Organisme : NIAID NIH HHS
ID : R21 AI136737
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008283
Pays : United States
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