Discovery and Characterization of Super-Enhancer-Associated Dependencies in Acute Myeloid Leukemia

Misregulation of genes that play an important role in transcription and chromatin biology is a salient feature of many hematological cancers, including acute myeloid leukemia (AML). Numerous genome-wide analyses in AML have provided evidence linking recurring genetic mutations to epigenomic alterations and disease-specific gene expression programs but the prognostic value and clinical utility of these findings remain unclear. Recently, a novel class of densely clustered cis-regulatory elements termed super-enhancers have emerged as key effectors initiating and maintaining cell type-specific gene expression in a variety of physiological and disease settings, including cancer. Tumor-specific super-enhancers regulate key oncogenes and other cancer-essential genes, providing a novel target discovery strategy for detecting both known and unrecognized cancer dependencies of high diagnostic and therapeutic value. Here we describe the discovery and characterization of super-enhancer domains across a cohort of nearly 50 AML patients and relevant normal hematopoietic stem and progenitor cell controls. We identified unique, clone-specific cancer targets encoding protein kinases, chromatin regulators, and lineage-specific transcription factors, including key drivers of AML such as FLT3, CDK6, and MYB. In addition, we have identified clusters of AML cases with shared super-enhancer domains suggesting convergence on common key drivers of AML. We provide the biological and disease relevance of super-enhancer-associated genes in the context of tumor cell state and drug-target discovery and establish a molecular rationale for developing therapies based on these new insights.