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Monkey business: Repurposing a protein from the simian immunodeficiency virus to enhance cytotoxic chemotherapy

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Science Translational Medicine  01 Feb 2017:
Vol. 9, Issue 375, eaam6051
DOI: 10.1126/scitranslmed.aam6051

Abstract

Cytarabine activity in acute myeloid leukemia blasts can be augmented by degrading the expression of a critical hydrolase.

Cytarabine, a deoxycytidine nucleoside analog, forms the backbone of most chemotherapy regimens for acute myeloid leukemia (AML) and has been used for over 40 years. Intracellular accumulation of its active metabolite, a deoxynucleoside triphosphate known as ara-CTP, causes leukemic cell death by interfering with DNA synthesis. The lack of response to cytarabine is among the major causes of treatment failure, yet the precise determinants of differential patient response remain undefined. A mechanistic understanding of factors responsible for interindividual differences in cytarabine sensitivity could improve AML patient outcomes, particularly if a clinically tractable approach could be found to enhance cytarabine sensitivity.

Herold, Rudd, and colleagues postulated that cytarabine sensitivity could be affected by endogenous cellular factors capable of hydrolyzing deoxynucleoside triphosphates. SAMHD1 (deoxynucleoside triphosphate triphosphohydrolase SAM domain and HD domain 1) was previously identified as an HIV restriction factor that is expressed in myeloid cells and that hydrolyzes dNTPs required for retroviral replication. The authors found that intracellular ara-CTP is depleted by activity of SAMHD1 in AML blasts. Recombinant SAMHD1 hydrolyzed ara-CTP in vitro, whereas abrogation of SAMHD1 expression or activity enhanced cytarabine-induced cytotoxicity in vitro and in mouse models of AML. The authors also found that SAMHD1 expression could be reduced by ex vivo treatment with the simian immunodeficiency virus protein Vpx, which was previously shown to target SAMHD1 for proteasomal degradation. This had the effect of sensitizing primary patient AML cells to cytarabine. Clinically, the authors found that SAMHD1 levels correlated with treatment failure in cohorts of pediatric and adult AML patients treated with high-dose but not low-dose cytarabine. A comparison with previously described factors involved in cytarabine metabolism showed that only SAMHD1 had a significant impact on survival.

Notably, Vpx treatment also augmented the sensitivity of healthy human hematopoietic stem/progenitor cells (HSPC) to cytarabine, and this finding urges caution in downstream clinical translation of this approach. The next step to be taken is to find clinically tractable approaches of degrading SAMHD1 specifically within leukemic cells in order to improve the long-term survival of patients with AML.

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