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CD36 has been identified as a potential therapeutic target both in the leukemic cells and in the tumor immune microenvironment. CD36 also plays a role in lipid metabolism of cancer associated T-cells leading to impaired cytotoxic CD8+ T-cell and enhanced Treg cell function. In acute myeloid leukemia (AML), we found that APOC2 acts with CD36 to promote leukemia growth by activating the LYN-ERK signaling. To establish CD36 as a viable therapeutic target in AML, we recently investigated whether targeting CD36 has any detrimental impact on normal hematopoietic cells. We compared B6.129S1-Cd36tm1Mfe/J Cd36 knockout (Cd36-KO) with C57BL/6J control (WT) mice (N=6 per group). Cd36-KO mice have normal blood counts except for lower red blood cells count (5.85 vs 6.93 (x 106/μL), P = 0.0332), hemoglobin (10.03 vs 11.35 (gr/dL), P = 0.0109), and hematocrit (31.67 vs 35.48 (%), P = 0.02) than WT mice, yet these values remained within the normal range. Cd36-KO mice exhibited similar spleen T cell phenotypes compared with the WT mice and expanded similarly in vitro in the presence IL2 and PHA. The in vitro expansion of hematopoietic stem and progenitor cells (HSPC) in HSPC expansion media containing SCF and TPO cytokines was also similar between Cd36-KO mice and WT mice. However, mouse colony forming cell assay using methylcellulose-based media showed that the HSPC of Cd36-KO mice resulted in 40% fewer colonies than WT mouse HSPC cells (P = 0.0003). However, when HSPC obtained from Cd36-KO and WT mice were transplanted in CD45.1 mice, their percentage of engraftment were not significantly different in the bone marrow (BM: KO vs WT: 64.92% vs 63.45%, P > 0.9999), spleen (40.88% vs 40.05%, P = 0.8413), and blood (83.47% vs 82.88%, P > 0.9999). To assess whether CD36 in the leukemia microenvironment has an impact on leukemia growth and progression, we injected 5 x 106 FLT3-ITD/MLL-PTD mouse leukemic cells via tail vein in either Cd36-KO mice (N = 5) or WT mice (N = 6) and compared the percentage of engraftment in their tissues. Cd36-KO mice exhibited similar leukemia engraftment in the BM (88.92% vs 86.38%, P = 0.0497), spleen (76.48% vs 68.10%, P = 0.1627), liver (16.12% vs 6.70%, P = 0.2521), and blood (16.33% vs 0.96%, P = 0.2504) compared with the WT group. Cd36-KO and WT mice developed similar leukemia burden when less aggressive models are used with the engraftment of 1 x 106 FLT3-ITD/MLL-PTD mouse leukemic cells. Altogether, our preliminary data suggest that loss of Cd36 may influence the hematopoietic stem cell and erythropoiesis yet have limited detrimental overall impact on normal hematopoiesis and leukemia microenvironment. Therefore, targeting CD36 in leukemic cells presents limited toxicity on normal hematopoiesis and therapeutic approaches to target this receptor present safe strategies to treat AML. Citation Format: Yiting Meng, Mateusz Pospiech, Atham Ali, Ritu Chandwani, Sandra Onyemaechi, George Yaghmour, Houda Alachkar. Functional characterization of the impact of CD36 deletion on normal hematopoiesis and the leukemia microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1732.