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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.
We report on the successful implementation and characterization of a cryogenic solid hydrogen target in experiments on high-power laser-driven proton acceleration. When irradiating a solid hydrogen filament of 10 μm diameter with 10-Terawatt laser pulses of 2.5 J energy, protons with kinetic energies in excess of 20 MeV exhibiting non-thermal features in their spectrum were observed. The protons were emitted into a large solid angle reaching a total conversion efficiency of several percent. Two-dimensional particle-in-cell simulations confirm our results indicating that the spectral modulations are caused by collisionless shocks launched from the surface of the the high-density filament into a low-density corona surrounding the target. The use of solid hydrogen targets may significantly improve the prospects of laser-accelerated proton pulses for future applications.