The leukemogenic TCF3-HLF fusion deregulates super-enhancers including a critical activation site conferring MYC transcriptional dependency. The leukemogenic TCF3-HLF fusion deregulates super-enhancers including a critical activation site conferring MYC transcriptional dependency

The chimeric transcription factor TCF3-HLF defines an incurable acute lymphoblastic leukemia subtype. Using genetic engineering in patient-derived cells, we demonstrate that TCF3-HLF interferes with differentiation and promotes self-renewal through its recruitment at hematopoietic stem cell/myeloid lineage associated (super-)enhancers to reprogram gene expression. TCF3- HLF hijacking of one HLF binding site in the MYC blood enhancer cluster is crucial for enhancer-promoter loop conformation at the MYC locus and leukemia propagation in vivo. TCF3-HLF pioneers the cooperation with ERG based on a conserved motif grammar, and recruits EP300, BRD3 and BRD4, conferring significant susceptibility to BET bromodomain inhibition. These results decipher the epigenetic function of TCF3-HLF providing a rationale to repurpose therapeutic agents to control this fatal leukemia.