Abstract T cells are very potent eliminators of residual cancer cells in children with leukemia after allogeneic hematopoietic stem cell transplant (alloHSCT) through the graft-versus-leukemia (GVL) effect. T cells are typically transfused into patients in the stem cell graft or as a separate donor lymphocyte infusion (DLI). The major limitation is that these same T cells can also attack and damage normal body tissues in the patient, causing graft-versus-host disease (GVHD). GVHD contributes to significant morbidity and mortality after alloHSCT. Although a variety of medications are available to treat GVHD, these medications also suppress the ability of T cells to mediate a beneficial GVL effect. The long-term objective of this proposal is to develop novel therapies that preserve the GVL benefit of alloHSCT while successfully preventing GVHD. Because GVHD produces inflammatory cytokines, such as gamma interferon (IFN), that activate the immune system, this project will utilize mouse models of alloHSCT to inhibit STAT1 signaling in plasmacytoid dendritic cells (pDCs) to make alloHSCT recipients resistant to the effects of IFN. Adoptively transferring STAT1-deficient pDCs, a novel cellular therapy, will allow the usage of a high dose of DLI to treat leukemia safely without causing GVHD. Lastly, it will also develop and screen a variety of approved drugs that target STAT1 on GVL activity using a relevant alloHSCT model with pediatric leukemia. The ultimate goal is to support the research priorities of the National Cancer Institute by developing research that will lead to novel therapies for leukemia. This proposal will provide the foundation for bringing drugs that target STAT1 forward to the clinic as a means of improving the safety and efficacy of alloHSCT, and ultimately improving survival in patients with leukemia.