SAMHD1 expression contributes to doxorubicin resistance and predicts survival outcomes in diffuse large B-cell lymphoma patients

Diffuse large B-cell lymphoma (DLBCL) is a commonly diagnosed, aggressive non-Hodgkin's lymphoma. While R-CHOP chemoimmunotherapy is potentially curative, about 40% of DLBCL patients will fail, highlighting the need to identify biomark ers to optimiz e management. SAMHD1 has a dNTPase-independent role in promoting resection to facilitate DNA double-strand break (DSB) repair by homologous recombination. We e v aluated the relationship of SAMHD1 le v els with sensitivity to DSB-sensitizing agents in DLBCL cells and the association of SAMHD1 expres- sion with clinical outcomes in 79 DLBCL patients treated with definitive therapy and an independent cohort dataset of 234 DLBCL patients. L o w SAMHD1 expression, Vpx-mediated, or siRNA-mediated degradation / depletion in DLBCL cells was associated with greater sensitivity to do x orubicin and PARP inhibitors. On Kaplan-Meier log-rank surviv al analy sis, lo w SAMHD1 e xpression w as associated with impro v ed o v erall sur- vival (OS), which on subset analysis remained significant only in patients with advanced stage (III-IV) and moderate to high risk (2-5 International P rognostic Inde x (IPI)). T he association of lo w SAMHD1 e xpression with impro v ed OS remained significant on multiv ariate analy sis independent of other adv erse f actors, including IPI, and was validated in an independent cohort. Our findings suggest that SAMHD1 expression mediates do x orubicin resistance and may be an important prognostic biomarker in advanced, higher-risk DLBCL patients.