Acute Myeloid Leukemia (AML) is a genetically and phenotypically heterogeneous white blood cell cancer with a poor prognosis and limited therapeutic options. For many decades the current standard of care has been an intensive chemotherapy regimen, to which only a fraction of patients respond and are physically able to withstand. However, the advent of deep genetic sequencing has led to the discovery of a number of mutational lesions targetable by small-molecule inhibitors, which more patients can tolerate. This dissertation demonstrates that AML drives in vivo T cell exhaustion, which is coordinated by multiple T cell receptor (TCR) activated transcription factors and BET proteins.