Enhancer remodeling drives MLL oncogene-dependent transcriptional dysregulation in leukemia stem cells [ChIP-seq]

Acute myeloid leukemia (AML) with MLL gene rearrangement (MLLr) comprises a cellular hierarchy in which subpopulations of cells with distinct immunophenotypes serve as functional leukemia stem cells (LSCs, c-Kit+) and mature AML cells (mAML, c-Kit-), respectively. They are maintained by a unique gene expression program and chromatin states, which are thought to reflect the actions of cis-regulatory elements with features of enhancers. Here, we delineate the active enhancer landscape and observe pervasive enhancer malfunction in MLLr LSCs. Reconstruction of regulatory networks revealed a master set of hematopoietic transcription factors (TFs). We show that EP300 is an essential transcriptional coregulator with these TFs for maintaining LSC oncogenic potential, as it controls essential gene expression through modulation of H3K27 acetylation and assessments of transcription factor dependencies. Moreover, the EP300 small molecule inhibitor A-485 affects LSC growth by targeting enhancer activity via histone acetyltransferase domain inhibition. Together, these data implicate a perturbed MLLr-specific enhancer accessibility landscape, suggesting the possibility for disruption of the LSC enhancer regulatory axis as a promising therapeutic strategy in AML. Examination of 3 different histone modifications in GMP, LSC, and mAML. Also examination of H3K27ac and P300 in LSC after A-485 treatment.