Abstract P37: Macrophage-Derived Deoxycytidine Drives Cytarabine Resistance in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) frequently develops resistance to chemotherapy, posing significant challenges to treatment. The bone marrow microenvironment is crucial in mediating drug resistance in hematological malignancies, though the underlying mechanisms remain poorly understood. In this study, we demonstrate that macrophages contribute to resistance against cytarabine (AraC) in AML, as evidenced by the increased sensitivity to AraC following macrophage depletion in murine AML models. In vitro experiments further reveal that this resistance is partly mediated by soluble factors secreted by macrophages. A whole-genome CRISPR screen identified deoxycytidine kinase (DCK) as a key target of these soluble factors in AML cells. Metabolic profiling pinpointed deoxycytidine (dC) as the primary soluble factor secreted by macrophages that inhibits DCK activity, thereby driving AraC resistance. Additionally, we found that macrophages express high levels of SAM and HD domain-containing protein 1 (SAMHD1), an enzyme in dC biogenesis, suggesting that macrophages are a significant source of dC in vivo. Collectively, our findings uncover a novel mechanism of AraC resistance in AML mediated by macrophage-derived dC and propose that targeting pyrimidine metabolism in macrophages could be a potential strategy to overcome this resistance. Citation Format: Chuqi Wang, Yuhan Wang, Camillo Benetti, Karanpreet Bhatia, Xiao Xian Lin, Shruti Bhatt. Macrophage-Derived Deoxycytidine Drives Cytarabine Resistance in Acute Myeloid Leukemia [abstract]. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85(15_Suppl):Abstract nr P37.