BET bromodomain inhibition: a potential therapeutic avenue in MEF2D-HNRNPUL1-rearranged B-cell acute lymphoblastic leukaemia

B-cell acute lymphoblastic leukemia harboring MEF2D-translocations represents an aggressive subtype with poor prognosis. MEF2D fusion proteins drive leukemogenesis via super enhancer mediated transcriptional dysregulation, making them promising target for epigenetic intervention. BET proteins, especially BRD4, are key regulators of oncogenic enhancer activity. Here, we explored the potential of BET protein inhibition as a targeted therapeutic strategy in MEF2D-HNRNPUL1 translocated B-ALL. Our study revealed that BET inhibitor inhibited proliferation and triggered apoptosis in leukemic cells, by targeting pre-BCR genes in addition to previously demonstrated targets, c-myc and IL-7R. A novel finding is that BET inhibitor induces DNA damage by downregulating DNA repair genes. These findings highlight that anti-leukemic activity of BET inhibitors offers a promising strategy to improve outcomes in this high-risk leukemia subtype.