Abstract CD36, a fatty acid translocase, is recognized as a potential therapeutic target in acute myeloid leukemia (AML), where its overexpression is associated with disease progression, yet its role in leukemogenesis remains to be elucidated. This study investigates the role of CD36 in leukemia initiation using the MLL-AF9 mouse model, where hematopoietic stem progenitor cells (HSPCs) from Cd36 knockout (KO) or wild-type (WT) mice were transduced with MLL-AF9 virus and evaluated for leukemogenic potential through in vitro and in vivo assays, and comprehensive transcriptomic, metabolomic, and immune profiling. Both Cd36KO and Cd36WT HSPCs transformed into leukemic cells, but Cd36 deletion led to a less aggressive leukemia phenotype, with reduced leukemia burden and extended median survival in sublethaly irradiated mice (15 vs. 22 days, P = 0.001). Leukemia engraftment was significantly higher in Cd36WT-MA9 compared with Cd36KO-MA9 transplanted mice in spleen (74.99% vs. 38.67%, P = 0.008) and blood (85.49% vs. 26.84%, P 0.001) relative to bone marrow (BM). Increased CD4 (13.93% vs. 36.78%, P = 0.025) and CD8 T cells (7.62% vs. 16.06%, P = 0.02) and less CD4CD25 T cells (34.53% vs. 19.24%, P = 0.006) were observed in mice engrafted with Cd36KO-MA9 cells compared with Cd36WT-MA9 mice. qPCR analysis shows elevated Gzmb (2.43-fold, P 0.001), and Tim3 (5.88-fold, P = 0.002) mRNA expression in Cd36WT-MA9 compared with Cd36KO-MA9 mice, while Foxp3, Lag3, and Pd1 showed no significant differences. A more pronounced phenotypic was observed in immunocompetent, non-irradiated mice; Cd36WT-MA9 cells displayed significantly greater leukemia engraftment (BM: 98.58% vs. 0.73%, P 0.0001; spleen: 64.60% vs. 0.79%, P 0.001, and blood: 89.08% vs. 10.20%, P = 0.014) compared with Cd36KO-MA9 cells. Cd36KO-MA9 mice showed enhanced immune responses with higher CD3+ (10.87% vs. 37.82%, P 0.001), CD4 (27.77% vs. 55.19%, P = 0.008), CD8 T cells (17.84% vs. 31.24%, P 0.001), and NK1.1 cells (14.47% vs. 29.83%, P 0.0001), but lower CD4CD25 (11.11% vs. 5.55%, P = 0.045), DN-T cells (51.95% vs. 10.46%, P 0.001), and CD25 DN T cells (17.77% vs. 4.00%, P 0.001) compared with Cd36WT-MA9 mice, suggesting Cd36 deletion reduces leukemia progression by enhancing anti-leukemic immunity. RNA-sequencing and gene set enrichment analysis indicated enrichment of inflammatory (TNFA, FDR 0.001) and metabolic pathways (oxidative phosphorylation, FDR 0.001) in Cd36WT-MA9 cells compared with Cd36KO-MA9 mice. Metabolomic analysis identified 124 metabolites, with Cd36KO-MA9 cells showing a significant increase in asparagine (10.00-fold, unadj P = 0.009) and a decrease in purine (7.68-fold, unadj P 0.0001) compared with Cd36WT-MA9 cells. While Cd36 deletion does not prevent leukemogenesis, it alters the leukemia immune microenvironment and slows leukemia progression, highlighting its role in modulating leukemia development. Citation Format: Yiting Meng, Wenda Zhu, Mateusz Pospiech, Long Huynh, Kalyani Divgi, Yiyu Xiao, Qianqian Peng, Nicholas A. Graham, Houda Alachkar. CD36 influences leukemia progression in MLL-AF9-driven AML by modulating the leukemia immune microenvironment abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7413.
Meng et al. (Fri,) studied this question.