Beyond the genome: Harnessing the power of super-enhancers for blood cancer

To continue to improve outcomes and quality of life for patients with haematological malignancies, we must look beyond the information encoded in DNA and past the well-mapped landscape of known genetic aberrations.

I believe the next frontier could lie not in the coding sequence itself, but in the dynamic regulatory networks of the non-coding genome that orchestrate gene expression – the epiregulome.

With more than 200 cell types comprising the human body, precise lineage-specific gene regulation is fundamental to maintaining cellular diversity. Recent breakthroughs have revealed that the guardians of cell identity often reside in the vast non-coding regions of the genome where clusters of enhancers – aptly named super-enhancers – exert extraordinary regulatory control. These powerful elements, first described in the baculovirus genome and later in mouse embryonic stem cells, coordinate the high-fidelity expression of genes that define cell identity.

But with great power comes vulnerability. Super-enhancers ensure robust and sustained expression of cell identity genes and tumour suppressors, protecting healthy cells from malignant transformation. However, this same power renders them susceptible to hijacking by cancer cells. In malignancies such as acute lymphoblastic leukaemia, super-enhancers activate proto-oncogenes, changing their original role and turning from genomic guardians into agents of disease.

Oncogenic hijacking

Over the past two decades, my research has explored how this reprogramming occurs. I look at how non-coding regions of the genome essential for normal development transform into drivers of oncogenic transcriptional programs.

The mechanisms underlying super-enhancer function are not fully elucidated. Their regulatory strength appears to depend on the deposition of broad epigenetic marks – such as the histone modification H3K4me3 – across gene bodies which enhance chromatin accessibility and facilitate sustained gene expression. When these marks are redirected toward proto-oncogenes, the result is aberrant activation and disease progression. Studies investigating these dual roles in regulating both cell identity, tumour suppressor genes and proto-oncogenes are still emerging, but the insights they offer are profound.

So why are certain super-enhancers more susceptible to oncogenic hijacking? Part of the answer lies in their genomic context. For instance, in B and T cells, super-enhancers orchestrate the complex recombination processes necessary for immunoglobulin and T-cell receptor maturation.

While essential for immune function, this inherent genomic plasticity also introduces risk – providing windows of opportunity for chromosomal rearrangements that place proto-oncogenes under the control of these powerful regulatory domains. The immunoglobulin heavy chain locus, for example, harbours four major super-enhancers capable of exerting control over vast genomic regions. Aberrant activation at any stage of B cell differentiation can lead to dysregulation of multiple proto-oncogenes, contributing to a broad spectrum of B cell malignancies.

Therapeutic target?

Research has already uncovered several hijacking events and their downstream effects – revealing dysregulated signalling pathways and therapeutic targets. Some inhibitors show promise in disrupting these pathways, yet cancer cells are experts at evolving resistance. They may activate compensatory mechanisms or acquire mutations in targeted proteins that render treatments ineffective.

So how do we outsmart these evolutionary escape routes? The answer may lie in targeting the very core of regulatory disruption.

Super-enhancers exhibit exquisite cell-type specificity and are acutely sensitive to changes in the concentrations of cell-type specific transcription factors and chromatin regulators. This specificity offers a strategic advantage: therapeutic targeting of leukaemia-specific super-enhancers could spare healthy cells, enabling precision medicine approaches that are both effective and less toxic.

By mapping and characterising the epigenomic landscape governed by super-enhancers, we can identify druggable vulnerabilities that drive leukaemic gene expression at its source rather than tackling the vast consequences of downstream changes in the transcriptome and proteome.

And there is another, hugely important reason to understand the epigenomic landscape here as well. It could be that these non-coding regulatory regions hold the key to more accurate risk stratification and prediction of treatment response, offering a paradigm shift in how we understand and treat haematological cancers.

The promise of super-enhancer biology is vast. As we expand our technical toolkit to interrogate the non-coding genome and decode its regulatory powers, we move closer to developing therapies that are not only more targeted but also gentler. Therapies that improve both survival and quality of life for patients due to cancer cell-specific targeting.

In doing so, we could find ourselves stepping boldly into a new era of cancer treatment, where the hidden architecture of gene regulation is no longer a mystery, but a roadmap to a brighter future for those affected by a cancer diagnosis.