SAMHD1 dysfunction impairs DNA damage response and increases sensitivity to PARP inhibition in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a clinically and genetically heterogenous disease. Recent next-generation sequencing (NGS) studies have uncovered numerous low-frequency mutated genes in CLL patients, with SAMHD1 emerging as a candidate driver gene. However, the biological and clinical implications of SAMHD1 mutations remain unclear. Using CRISPR/Cas9, we generated CLL models to investigate the impact of SAMHD1 deficiency on pathogenesis and explore therapeutic strategies. Moreover, we performed NGS in treatment-naïve CLL patients to characterize SAMHD1 mutations and employed RNA-sequencing to evaluate their clinical significance. Our study shows that SAMHD1 inactivation impairs the DNA damage response by reducing homologous recombination efficiency through BRCA1 and RAD51 dysregulation. Importantly, SAMHD1 colocalizes with BRCA1 at DNA damage sites in CLL cells. This research also identifies that SAMHD1-mutated cells are more sensitive to PARP inhibition. Clinically, SAMHD1 dysfunction negatively impacts clinical outcome of CLL cases: SAMHD1 mutations reduce failure-free survival (median 46 vs 57 months, p = 0.033), while low SAMHD1 expression associates with shorter time to first treatment (median 47 vs 77 months; p = 0.00073). Overall, this study elucidates that SAMHD1 dysfunction compromises DNA damage response mechanisms, potentially contributing to unfavorable clinical outcomes in CLL, and proposes PARP-inhibitors as a potential therapeutic approach for SAMHD1-mutated CLL cells.