TY  - JOUR
A1  - Rothenburger, Tamara
A1  - McLaughlin, Katie-May
A1  - Herold, Tobias
A1  - Schneider, Constanze
A1  - Oellerich, Thomas
A1  - Rothweiler, Florian
A1  - Feber, Andrew
A1  - Fenton, Tim
A1  - Wass, Mark N.
A1  - Keppler, Oliver Till
A1  - Michaelis, Martin
A1  - Cinatl, Jindrich
T1  - SAMHD1 is a key regulator of the lineage-specific response of acute lymphoblastic leukaemias to nelarabine
T2  - Communications biology
N2  - 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.
KW  - Acute lymphocytic leukaemia
KW  - Chemotherapy
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/54732
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-547328
SN  - 2399-3642
N1  - Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
VL  - 3
IS  - 1, Art. 324
SP  - 1
EP  - 10
PB  - Springer Nature
CY  - London
ER  -