Super enhancers as master gene regulators in the pathogenesis of hematologic malignancies.

ABSTRACT

Transcriptional deregulation of multiple oncogenes, tumor suppressors and survival pathways is a cancer cell hallmark. Super enhancers (SE) are long stretches of active enhancers in close linear proximity that ensure extraordinarily high expression levels of key genes associated with cell lineage, function and survival. SE landscape is intrinsically prone to changes and reorganization during the course of normal cell differentiation. This functional plasticity is typically utilized by cancer cells, which remodel their SE landscapes to ensure oncogenic transcriptional reprogramming. Multiple recent studies highlighted structural genetic mechanisms in non-coding regions that create new SE or hijack already existing ones. In addition, alterations in abundance/activity of certain SE-associated proteins or certain viral infections can elicit new super enhancers and trigger SE-driven transcriptional changes. For these reasons, SE profiling emerged as a powerful tool for discovering the core transcriptional regulatory circuits in tumor cells. This, in turn, provides new insights into cancer cell biology, and identifies main nodes of key cellular pathways to be potentially targeted. Since SEs are susceptible to inhibition, their disruption results in exponentially amassing 'butterfly' effect on gene expression and cell function. Moreover, many of SE elements are druggable, opening new therapeutic opportunities. Indeed, SE targeting drugs have been studied preclinically in various hematologic malignancies with promising effects. Herein, we review the unique features of SEs, present different cis- and trans-acting mechanisms through which hematologic tumor cells acquire SEs, and finally, discuss the potential of SE targeting in the therapy of hematologic malignancies.