Acute myeloid leukemia (AML) is a poor-prognosis hematological malignancy characterized by differentiation blockade and uncontrolled proliferation. Epigenetic programs influence AML cell fate decisions, and their mis-regulation can promote differentiation arrest. It is therefore of paramount importance to identify the regulators of AML cell differentiation and understand the mechanisms by which they repress myeloid transcriptional programs. Here, we performed a cell-fate selection CRISPR screen for chromatin factors whose inhibition promotes AML cell differentiation. We found that the histone acetyltransferase KAT6A is a critical driver of the differentiation block, and that genetic and chemical inhibition of KAT6A markedly de-repressed latent myeloid maturation programs, most commonly in MLL-rearranged AML. Inhibition of KAT6A catalysis reduced self-renewal, induced cell cycle arrest, and extinguished long-term proliferative capacity of AML cells. Through ChIP-seq, RNA-seq, and biochemical approaches, we found that KAT6A is the likely initiator of a newly-described "writer-reader" transcriptional control module in AML. In this model, KAT6A catalyzes promoter H3K9 acetylation, which recruits the H3K9ac reader ENL, leading to Super-elongation Complex recruitment and release of paused RNA PolII at oncogenic loci such as MYC. KAT6A is elevated in human AMLs compared to matched normal tissue, and its downregulation correlates with monocytic differentiation transcriptional programs in clinical AML datasets. These findings suggest the potential of targeting KAT6A and ENL to disrupt this writer-reader module and ablate downstream MYC transcriptional programs in MLL-rearranged AML. Additionally, we interrogate the fundamental mechanisms of control of the cellular decision-making process in myeloid lineage cells. Using an in vitro inducible neutrophil differentiation model, we identify a “point of no return” in the differentiation timecourse beyond which the cells become unable to return to the progenitor state. We find that global condensing of chromatin and epigenetic silencing of progenitor-state transcription factors fix cells into the differentiated state. These findings have significant implications for therapeutic approaches such as differentiation therapy that aim to target aberrant cell fate states. ​