Macrophage-secreted Pyrimidine Metabolites Confer Chemotherapy Resistance in Acute Myeloid Leukemia (AML)

Wang, C.; Wang, Y.; Benetti, C.; Lin, X. X.; Dasdemir, E.; Hyrossov, P.; Tan, J. Y. M.; Ayoub, E.; Bhatia, K. S.; Lim, F. Q.; Li, Y.; Zhao, Z.; Mohamed, A. M. M.; Lee, S. Y.; Rohlena, J.; Pecot, C. V.; Andreeff, M.; Rohlenova, K.; Abbas, H. A.; Bhatt, S.

doi:10.1101/2025.11.01.686055

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bioRxiv · 10.1101/2025.11.01.686055

Macrophage-secreted Pyrimidine Metabolites Confer Chemotherapy Resistance in Acute Myeloid Leukemia (AML)

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Abstract

The tumor microenvironment (TME) programs cancer cells to influence therapeutic responses. Macrophages residing in TME switch from pro-phagocytic to tumor-promoting and immunosuppressive phenotypes as cancer develops. While these pro-tumor functions of macrophages are associated with poor outcomes, the underlying mechanisms by which bone-marrow (BM)-associated macrophages fuel myeloid malignancy and their precise contribution to relapse remain undissected. Here, we show expansion of monocyte/macrophage population in leukemia patients post-chemotherapy relapse, and spatial proximity of macrophages to leukemia blasts in the BM niche. This proximity proved functionally consequential--depletion of macrophages delayed leukemia relapse post cytarabine (AraC), a frontline chemotherapy, in patient-derived xenografts (PDX) and syngeneic leukemia models. Mechanistically, a pyrimidine metabolite, deoxycytidine (dC), secreted by BM macrophages, is taken up by leukemia cells to directly inhibit deoxycytidine kinase (DCK) to hamper AraC activation and subsequent resistance in a cell non-autonomous manner. Diagnosis AML patients exhibited significantly higher circulating dC levels than healthy donors, and dC levels further increased following chemotherapy. SAMHD1, which catalyzes deoxynucleoside triphosphates (dNTPs) into deoxynucleoside, was highly abundant in macrophages and mediated dC accumulation. Blockade of dC production in mouse and human macrophages via genetic and pharmacological inhibition of SAMHD1 or DHODH, a critical enzyme in pyrimidine synthesis, restored AraC sensitivity. Combination with DHODH inhibitors significantly delayed AraC relapse in human PDX and mouse syngeneic AML models. Collectively, we identify a metabolic immune-leukemia crosstalk in which SAMHD1high macrophages mediates chemoresistance by secreting pyrimidine metabolites and propose macrophage metabolic reprogramming as a tractable strategy to overcome TME-driven chemoresistance in myeloid leukemia.

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Wang, C., Wang, Y., Benetti, C., Lin, X. X., Dasdemir, E., Hyrossov, P., Tan, J. Y. M., Ayoub, E., Bhatia, K. S., Lim, F. Q., Li, Y., Zhao, Z., Mohamed, A. M. M., Lee, S. Y., Rohlena, J., Pecot, C. V., Andreeff, M., Rohlenova, K., Abbas, H. A., Bhatt, S.. 2025-11-03. Macrophage-secreted Pyrimidine Metabolites Confer Chemotherapy Resistance in Acute Myeloid Leukemia (AML). https://doi.org/10.1101/2025.11.01.686055

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