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SAMHD1 is a key regulator of the lineage-specific response of acute lymphoblastic leukaemias to nelarabine
- Source :
- Communications Biology, Vol 3, Iss 1, Pp 1-10 (2020), Communications Biology, Comm. Biol. 3:324 (2020)
- Publication Year :
- 2020
- Publisher :
- Nature Publishing Group, 2020.
-
Abstract
- The nucleoside analogue nelarabine, the prodrug of arabinosylguanine (AraG), is effective against T-cell acute lymphoblastic leukaemia (T-ALL) but not against B-cell ALL (B-ALL). The underlying mechanisms have remained elusive. Here, data from pharmacogenomics studies and a panel of ALL cell lines reveal an inverse correlation between nelarabine sensitivity and the expression of SAMHD1, which can hydrolyse and inactivate triphosphorylated nucleoside analogues. Lower SAMHD1 abundance is detected in T-ALL than in B-ALL in cell lines and patient-derived leukaemic blasts. Mechanistically, T-ALL cells display increased SAMHD1 promoter methylation without increased global DNA methylation. SAMHD1 depletion sensitises B-ALL cells to AraG, while ectopic SAMHD1 expression in SAMHD1-null T-ALL cells induces AraG resistance. SAMHD1 has a larger impact on nelarabine/AraG than on cytarabine in ALL cells. Opposite effects are observed in acute myeloid leukaemia cells, indicating entity-specific differences. In conclusion, SAMHD1 promoter methylation and, in turn, SAMHD1 expression levels determine ALL cell response to nelarabine.<br />Rothenburger et al. combine the analysis of data from large pharmacogenomics screens with cell line experiments to elucidate mechanisms behind nelarabine resistance in acute lymphoblastic leukaemia (ALL). They identify low expression of the dNTP hydrolase SAMHD1 as a determinant of nelarabine sensitivity, suggesting the enzyme as a biomarker.
- Subjects :
- 0301 basic medicine
RM
Medicine (miscellaneous)
Antineoplastic Agents
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
General Biochemistry, Genetics and Molecular Biology
Article
Transcriptome
SAM Domain and HD Domain-Containing Protein 1
03 medical and health sciences
0302 clinical medicine
Cell Line, Tumor
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
hemic and lymphatic diseases
medicine
Biomarkers, Tumor
Humans
Chemotherapy
ddc:610
Promoter Regions, Genetic
lcsh:QH301-705.5
Acute lymphocytic leukaemia
Nucleoside analogue
Chemistry
Gene Expression Regulation, Leukemic
Prodrug
DNA Methylation
030104 developmental biology
lcsh:Biology (General)
Cell culture
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
DNA methylation
Nelarabine
Cytarabine
Cancer research
Arabinonucleosides
General Agricultural and Biological Sciences
Nucleoside
medicine.drug
SAMHD1
Subjects
Details
- Language :
- English
- ISSN :
- 23993642
- Volume :
- 3
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Communications Biology
- Accession number :
- edsair.doi.dedup.....b4b71e6aa76364b58b628d2e235b3781