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Enhancer dysfunction in leukemia

Anand S. Bhagwat, Bin Lu and Christopher R. Vakoc

Abstract

Hematopoietic cancers are often initiated by deregulation of the transcriptional machinery. Prominent among such regulators are the sequence-specific DNA-binding transcription factors (TFs), which bind to enhancer and promoter elements in the genome to control gene expression through the recruitment of cofactors. Remarkably, perturbing the function of even a single TF or cofactor can modulate the active enhancer landscape of a cell and, conversely, knowledge of the enhancer configuration can be used to discover functionally important TFs in a given cellular process. Our expanding insight into enhancer function can be attributed to the emergence of genome-scale measurements of enhancer activity, which can be applied to virtually any cell type to expose regulatory mechanisms. Such approaches are beginning to reveal the abnormal enhancer configurations present in cancer cells, thereby providing a framework for understanding how transcriptional dysregulation can lead to malignancy. Here, we review the evidence for alterations in enhancer landscapes contributing to the pathogenesis of leukemia, a malignancy in which enhancer-binding proteins and enhancer DNA itself are altered via genetic mutation. We will also highlight examples of small-molecules that reprogram the enhancer landscape of leukemia cells in association with therapeutic benefit.

  • Submitted November 29, 2017.
  • Accepted February 5, 2018.