Abstract Acute myeloid leukemia (AML) is an aggressive myeloid lineage cancer with limited treatment options. Single-agent treatments with targeted inhibitors have resulted in some disease remissions, however, resistance almost always develops, prompting development of combinatorial treatment strategies. Studies have shown that AML patients exhibit markers of immune suppression such as increased levels of exhausted T cells (PD1/LAG3+) as well as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs)1. Inhibitors targeting the BET family, which are histone readers, have been shown to increase IFNy and IL-2 production in T cells by inhibiting BATF—a known negative regulator of TCF1, as well as decrease PD-L12–4. We, therefore, hypothesized that combining BRD4i and anti-PD1 would synergize by modulating both tumor intrinsic biology (though MYC reduction) and boosting T cell activity. We have characterized a FLT3-ITD/TET2/Lys-Cre mouse model of AML and observed significantly increased numbers of PD1+/TIM3+/TCF1− T cells, Tregs, and MDSCs when compared to healthy mice. T cells derived from mice with AML have significantly reduced T cell proliferation upon co-stimulation with CD3 and CD28. Ex vivo treatment with BRD4i + aPD1 significantly increased T cell proliferation in AML mice and increased TCF1 expression in a dose dependent manner. In vivo treatment with BRD4i + aPD1 showed enhanced reduction of leukemic blasts, reduced PD-L1, and increased CD8+ T cell infiltration into the bone marrow. Our work highlights the efficacy of this novel drug combination in targeting tumor intrinsic and extrinsic factors in AML and identifies a potential novel role for BRD4 in regulating TCF1 expression in T cells.