In the current studies, we demonstrate with murine models of GVHD that Pan-STAT3 deficiency (STAT3–/–), but not Mito-STAT3 deficiency, in donor T cells induces only mild and reversible acute GVHD while preserving GVL activity that eliminates BCL1 and even non-GVL susceptible ALL cells in a donor T cell dose-dependent manner. Here, STAT3 is linked to acute lymphoblastic leukemia.