Wild-type SAMHD1 functions and predicted functional consequence of SAMHD1 mutations in CLL. (A) Structure and cellular functions of wild-type SAMHD1. Representative schematic of the important domains of SAMHD1. The enzymatic activity of SAMHD1 is promoted by the HD domain. SAMHD1 degrades dNTPs into deoxynucleosides (dN) and inorganic triphosphates (PPP). Low levels of dNTPs decrease DNA synthesis, slow down cell cycle progression, promote apoptosis, and favor DNA repair. SAM, sterile α motif; P, putative phosphorylation site. (B) Predicted functional consequence of SAMHD1 mutations in CLL. SAMHD1 loss of function is predicted to result in increased dNTP cellular levels, DNA synthesis, cell cycle progression, and ultimately, proliferation, survival, and chemoresistance.