Super-Enhancers Dysregulations in Hematological Malignancies

Abstract

Hematological malignancies affecting either the lymphoid or the myeloid lineages involve epigenetic mutations or dysregulation in the majority of cases. These epigenetic abnormalities can affect regulatory elements in the genome and, particularly, enhancers. Recently, large regulatory elements known as super-enhancers, initially identified for their critical roles in cell-type specific expression regulation of genes controlling cell identity, have been shown to also be involved in tumorigenesis in many cancer types and hematological malignancies via the regulation of numerous oncogenes, including MYC. In this review, we highlight the existing links between super-enhancers and hematological malignancies, with a particular focus on acute myeloid leukemia, a clonal hematopoietic neoplasm with dismal outcomes, resulting in an uncontrolled proliferation of myeloblasts, abnormally blocked during differentiation and accumulating within the patient's bone marrow. We report recent works, performed during the last few years, treating this subject and consider the possibility of targeting oncogenic regulatory elements, as well as the effectiveness and limitations reported so far for such strategies.

Keywords: acute myeloid leukemia; enhancer hijacking; enhancers; hematological malignancies; leukemia; regulatory elements; super-enhancers.

Figure 1

Definition of super-enhancers. (A) Steps of identification and ranking of super-enhancers: reads from ChIP-seq for enhancer specific factors (such as MED1, BRD4) or histone modifications (H3K27ac, H3K4me1) are mapped to the reference genome and specific enrichment peaks are determined bioinformatically, then peaks closer than 12.5 kb are stitched together and the overall read signal intensity within these stitched areas is counted. Stitched regions are finally ranked by signal intensity, and super-enhancers are defined as regions whose intensity is above the tangent of slop 1. (B) Super-enhancers, as clusters of enhancers, are larger, present a higher TF and RNA pol II binding density, and induce a higher gene transcription compared to regular enhancers.

Figure 2

Loop extrusion model: Enhancer-promoter interactions through chromatin loops formation. (A) Cohesin rings are loaded onto chromatin by the NIPBL-MAU2 protein complex, at the base of the future loop. Some papers suggest that chromatin is actively extruded through the loop by the action of SMC cohesins. (B) The encounter of cohesin and CTCF proteins on each side of the loop is thought to block the progression of the loop extrusion. Another hypothesis further proposes that transcription factors, accumulating within the enhancer, could then be ‘exchanged’ or transferred between enhancer and promoter, through the proximity allowed by the loop. Such interactions could facilitate the recruitment of the transcriptional machinery, as well as RNA pol II, at the target gene promoter. (C) The increased concentration of transcription factors at gene promoters permitted by enhancer and RNA pol II recruitment ultimately results in a stronger transcription of cognate genes.

Figure 3

Indels inducing the introduction of MYB binding sites near TAL1. Somatic mutations acquired within a SE located near the TAL1 oncogene allow the production of MYB binding sites. Accumulation of MYB at these sites is responsible for the recruitment of p300 and CBP, leading to the deposition of H3K27ac marks and SE activation. Altogether, this results in the overexpression of the associated gene, here being TAL1.

Figure 4

Super-enhancer hijacking by ETO2-GLIS2 fusion. (A) In normal hematopoietic stem and progenitor cells, PDGFRA gene is not expressed and KIT expression is mainly driven by an enhancer located 3′ of its transcription termination site. (B) In AMKL blasts, ETO2-GLIS2 fusion is able to bind and hijack a de novo super-enhancer, termed SEKIT. This leads to the abnormal activation of SEKIT and the subsequent expression of two tyrosine kinase encoding genes, KIT and PDGFRA, involved in ETO2-GLIS2⁺ AMKL proliferation.