Hematopoietic stem cell transplantation (HSCT) is considered the gold standard for treatment of hematologic malignancies like leukemia. The rationale for the preferred strategy of using HSCT is based on the persistence of malignant stem cells that are capable of self-renewing and resistant to the cytotoxic effects of chemotherapy leading to disease relapse, and the benefits derived from the destruction of these cancer stem cells by the donor's immune system. One major hurdle, which has been hampering scientific and clinical advance in the leukemia HSCT field, is the frequently observed anergy or exhaustion of donor-derived anti-tumor T cells after exposure to the intratumoral microenvironment. Bone marrow (BM) mesenchymal niche cells may drive tissue failure and malignant transformation in the hematopoietic system. While bi-directional crosstalk between mesenchymal niche and leukemic cells including dormant leukemic stem cells (LSCs) is well documented, specific interactions between leukemic mesenchymal niche and donor hematopoietic stem and progenitor cells (HSPCs) remain poorly understood. We used unbiased metabolomics and transcriptomics to study the interaction between leukemic mesenchymal niche and donor HSPCs, and identified a novel COX2/PG/NR4A/WNT immunometabolism-regulatory axis, connecting inflammation, cellular metabolism and cancer immunity. We hypothesize that the AML-MSC COX2-PG signaling axis regulates donor anti-leukemia immunity involving a pathway hierarchy in which the leukemic mesenchymal COX2-PG secretome signals to NR4A TFs, which then activates WNT/?-catenin signaling to repress anti-leukemia T effector cells. The goals of the project are: (1) molecular and genetic dissection of the AML-MSC secretome regulatory axis in the context of leukemic mesenchymal niche-donor HSPC crosstalk, and (2) functional assessment of this novel immunometabolic regulatory axis in leukemia progression. To achieve these goals, we will first employ molecular and genetic approaches to determine the mechanistic link between leukemic mesenchymal COX2-PG secretome and the role of NR4A-WNT crosstalk in the formation and function of leukemia-reactive cytotoxic T- lymphocytes, and the contribution of the NR4A-WNT signaling to donor anti-leukemia immunity. We will then utilize an AML xenotransplant model and two pre-leukemic models to investigate the underlying mechanisms by dissecting the link between leukemic BM niche-driven COX2/PG/NR4A/WNT signaling and leukemia progression with specific focus on WNT-mediated GVL attenuation and leukemia progression. Successful completion of the proposed study will not only advancing our understanding of mechanisms governing recipient niche-donor cellular crosstalk in leukemia HSCT, but also leading to a new avenue of research designed to target the novel AML-MSC secretome regulatory axis for developing innovative therapeutic strategies in leukemia and other hematologic malignancies.