Deregulation of enhancer structure, function, and dynamics in acute lymphoblastic leukemia

Abstract

Enhancers control dynamic changes in gene expression and orchestrate the tightly controlled transcriptional circuitries that direct and coordinate cell growth, proliferation, survival, lineage commitment, and differentiation during lymphoid development. Enhancer hijacking and neoenhancer formation at oncogene loci, as well as aberrant activation of oncogene-associated enhancers, can induce constitutive activation of self-perpetuating oncogenic transcriptional circuitries, and contribute to the malignant transformation of immature lymphoid progenitors in acute lymphoblastic leukemia (ALL). In this review, we present recent discoveries of the role of enhancer dynamics in mouse and human lymphoid development, and discuss how genetic and epigenetic alterations of enhancer function can promote leukemogenesis, and potential strategies for targeting the enhancer machinery in the treatment of ALL.

Keywords: acute lymphoblastic leukemia; chromatin topology; enhancer; lymphoid development.

Figure 1.. Regulation of gene expression by enhancers.

Schematic representation of enhancer-promoter interaction by cohesin-mediated chromatin looping. Eukaryotic transcription factors occupy regulatory elements in enhancer and promoter sequences to recruit the Mediator complex, which in turn, induces RNA polymerase II (RNAPII) recruitment and activation. This figure was created using  BioRender (https://biorender.com/).

Figure 2.. Pioneer transcription factors induce nucleosome remodeling and facilitate transcription factor binding for enhancer activation.

a, Inactive enhancer closed chromatin configuration. b, Binding of pioneering transcription factors capable of recruiting nucleosome repositioning complexes and histone modifying enzymes favor an open chromatin configuration. c, Active enhancers are characteristically nucleosome free, show high levels of histone H3 lysine 27 acetylation (H3K27ac) marks and are occupied by multiple transcription factors that cooperatively control gene expression in association with promoter regulatory sequences. Arrows indicate nucleosome repositioning. This figure was created using  BioRender (https://biorender.com/).

Figure 3.. Mechanisms of enhancer deregulation in acute lymphoblastic leukemia (ALL).

Schematic representation of different mechanisms involved in aberrant enhancer-driven activation of transcription factor oncogenes (MYC and TAL1) in T-cell acute lymphoblastic leukemia (T-ALL). a, Chromosomal translocations involving the TCRA/D locus and the MYC oncogene place strong T-cell specific enhancers in the vicinity of the MYC locus overriding physiologic control by the thymocyte-specific N-Me enhancer in T-ALL. BENC: enhancer cluster responsible for expression of MYC in stem cells and non-T-cell hematopoietic progenitors in mice. N-Me: NOTCH1 activated enhancer responsible for MYC expression in mouse immature thymic progenitors and in mouse and human T-ALL. b, Duplication of the N-Me enhancer favors deregulated MYC expression in about 5% of T-ALL samples [43]. c, Increased NOTCH signaling --most commonly resulting from activating mutations in the NOTCH1 gene -- induce aberrantly high N-Me-driven MYC expression in over 60% of T-ALLs [43]. d, Chromosomal translocations involving the TCRA/D locus and the TAL1 oncogene place strong T-cell specific enhancers in the vicinity of the TAL1 locus, normally expressed in stem cells and erythroid precursors, but not in T cell progenitors [63]. e, Focal deletions in the STIL-TAL1 intergenic region generate a STIL-TAL1 fusion transcript driven by the STIL promoter with consequent aberrant expression of the TAL1 protein in 15–30% of T-ALL cancers [63]. f, Mutations in the STIL-TAL1 intergenic region generate a novel MYB binding site with neoenhancer function driving aberrant expression of TAL1 in 5% of T-ALL cases [70]. This figure was created using  BioRender (https://biorender.com/).