RT Journal Article
SR Electronic
T1 SAMHD1 is a key regulator of the lineage-specific response of acute lymphoblastic leukaemias to nelarabine
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 863183
DO 10.1101/863183
A1 Tamara Rothenburger
A1 Katie-May McLaughlin
A1 Tobias Herold
A1 Constanze Schneider
A1 Thomas Oellerich
A1 Florian Rothweiler
A1 Andrew Feber
A1 Tim R. Fenton
A1 Mark N. Wass
A1 Oliver T. Keppler
A1 Martin Michaelis
A1 Jindrich Cinatl, jr.
YR 2019
UL http://biorxiv.org/content/early/2019/12/03/863183.abstract
AB The nucleoside analogue nelarabine, the prodrug of arabinosylguanine (AraG), has been known for decades to be effective against acute lymphoblastic leukaemias of T-cell (T-ALL), but not of B-cell (B-ALL) origin. The mechanisms underlying this lineage-specific drug sensitivity have remained elusive. Data from pharmacogenomics studies and from a panel of ALL cell lines revealed an inverse correlation of SAMHD1 expression and nelarabine sensitivity. SAMHD1 can hydrolyse and thus inactivate triphosphorylated nucleoside analogues. Transcriptomic and protein expression profiling of cell lines and patient-derived leukaemic blasts revealed lower SAMHD1 abundance in T-ALL than in B-ALL. Mechanistically, SAMHD1 promoter methylation strongly correlated with suppressed SAMHD1 expression, while T-ALL cells did not display increased global DNA methylation. Targeted SAMHD1 degradation using virus-like particles containing Vpx sensitised B-ALL cells to AraG, while ectopic SAMHD1 expression in SAMHD1-null T-ALL cells induced AraG resistance. SAMHD1 had a larger impact on cytarabine activity than on nelarabine/ AraG activity in acute myeloid leukaemia (AML) cells, but more strongly affected nelarabine/ AraG activity in ALL cells. This indicates a critical role of the cancer entity. In conclusion, lineage-specific differences in SAMHD1 promoter methylation and, in turn, SAMHD1 expression levels determine ALL cell response to nelarabine. SAMHD1 is a potential biomarker for the identification of ALL patients likely to benefit from nelarabine therapy and a therapeutic target to overcome nelarabine resistance.