Super-Enhancer Landscapes Specify Molecular Subtypes And Novel Targets In Acute Myeloid Leukemia

AML is a highly genotypically and phenotypically heterogeneous cancer with many subtypes of the disease currently lacking clear targeted therapies. While several genetic alterations currently serve to stratify patients into prognostic subgroups and guide treatment decisions, the classification and treatment options for AML patients remain unsatisfactory. Numerous genome-wide analyses have provided evidence linking recurring genetic mutations in de novo AML to perturbations in epigenomic signaling, transcriptional regulation, and post-transcriptional mRNA processing, indicating that misregulation of gene expression is a key molecular feature of AML pathogenesis yet the diagnostic 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 expression of key oncogenes and other cancer-essential genes, providing a novel 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 large cohort of AML patients and relevant normal hematopoietic stem and progenitor cell controls. To this end, we profiled over 60 primary samples at both the level of epigenomic activity and transcript abundance and identify transcriptionally hyperactive regions in AML patients compared to normal healthy donors. By combining patient-specific super-enhancer landscapes with gene expression profiles, we elucidate the transcription factor repertoires controlling chromatin dynamics and lineage specification in cellular derivatives of normal hematopoietic development and purified AML samples. Further analyses yield a striking delineation of disease-unique transcriptional subtypes which are specified by distinct patterns of super-enhancers at well-known AML-related genes such as HOXA9, MEIS1, ETV6, and HOXB3. In addition, we identify clusters of AML cases with shared super-enhancer domains suggesting convergence on common key drivers of AML. Together, our results provide the biological and disease relevance of super-enhancers in the context of normal and tumor cell states and demonstrate how the comprehensive mapping of gene regulatory elements elucidate clinically relevant subtypes and new therapeutic targets in AML. Citation Format: Matthew Eaton, Ryan Corces-Zimmerman, Jeremy Lopez, Christian Fritz, Eric Olson, Ravindra Majeti, Jakob Loven. Super-enhancer landscapes specify molecular subtypes and novel targets in acute myeloid leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2212. doi:10.1158/1538-7445.AM2015-2212