SAMHD1 Limits the Effectiveness of Cytarabine in AML

Standard therapy for acute myeloid leukemia (AML) includes the cytidine analog cytarabine (Ara-C), which is converted into a triphosphate metabolite (Ara-CTP) that inhibits DNA synthesis. Although Ara-C induces remissions in many cases, some patients do not respond, and a significant number of patients relapse with refractory disease. Identification of predictive biomarkers of sensitivity to Ara-C therapy and potential therapeutic targets in Ara-C–refractory AML would have the potential to improve stratification and management of patients with AML. Schneider, Oellerich, Baldauf, Schwarz, and colleagues hypothesized that the sterile alpha motif and histidine-aspartic domain-containing protein 1 (SAMHD1), a deoxyribonucleoside triphosphate (dNTP) triphosphohydrolase, might enhance the efficacy of Ara-C by decreasing levels of dNTPs that compete with Ara-C for incorporation into newly synthesized DNA in rapidly proliferating cells. Contrary to this hypothesis, however, SAMHD1 expression was inversely correlated with Ara-C cytotoxicity. Moreover, depletion of SAMHD1 sensitized AML cell lines and human AML blasts to Ara-C, resensitized Ara-C–resistant human AML cell lines to Ara-C, and significantly prolonged overall survival of mice transplanted with AML that were treated with Ara-C. SAMHD1 deficiency resulted in significantly increased levels of Ara-CTP, suggesting that SAMHD1 modulates levels of the active Ara-C metabolite in AML cells. Indeed, in vitro enzyme assays showed that SAMHD1 hydrolyzes Ara-CTP to Ara-C, explaining the reduced Ara-CTP levels in SAMHD1-expressing AML cells. In a retrospective analysis of a cohort of adult patients with AML who were treated with Ara-C, SAMHD1 expression levels at diagnosis were significantly higher in patients who did not achieve complete remission, and high SAMHD1 expression was predictive of worse event-free, relapse-free, and overall survival. In addition to identifying SAMHD1 as a potential predictive biomarker of Ara-C sensitivity in patients with AML, these findings suggest that strategies to reduce SAMHD1 levels or inhibit its enzymatic activity may enhance Ara-C cytotoxicity in AML.

Schneider C, Oellerich T, Baldauf HM, Schwarz SM, Thomas D, Flick R, et al. SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia. Nat Med 2016 Dec 19 [Epub ahead of print].