Short Circuit: Drugging the super-enhancer network in AML

Acute Myeloid Leukemia (AML) has one of the worst prognoses of haematological cancers. It frequently results in post-treatment relapse due to its complex clonal heterogeneity allowing for the expansion of minimal residual disease populations. Therefore, targeting transcriptional pathways common across genetically diverse clones, rather than the dominant clonal genotype, is an avenue that demands exploration. Transcription factor pathways are imminently druggable due to an expanding library of epigenetic inhibitor compounds, however in order to effectively implement this approach, there must first be a molecular understanding of patient-specific transcriptional circuits. I propose to define the transcriptional circuitry of primary patient AML through super enhancer mapping, using a state-of-the-art technique called CUT&Tag. This strategy avoids artefacts of immortal cell lines and will identify candidate transcription factors (TFs) responsible for leukemic cell fate. Using Hi-ChIP, I will define the mechanisms of action of these TFs, including identification of their leukemic dependency, target genomic sites, and contribution to super enhancer-promoter contacts. Finally, I will ascertain the interactome of these TFs to identify co-regulator proteins which can be targeted chemically. Through this, I will target pan-clonal transcriptional networks to pair patients with appropriate repurposed epigenetic inhibitors for future therapeutic benefit.