The Leukemogenic TCF3-HLF Complex Rewires Enhancers Driving Cellular Identity and Self-Renewal Conferring EP300 Vulnerability

Cancer Cell. 2019 Dec 9;36(6):630-644.e9. doi: 10.1016/j.ccell.2019.10.004. Epub 2019 Nov 14.


The chimeric transcription factor TCF3-HLF defines an incurable acute lymphoblastic leukemia subtype. Here we decipher the regulome of endogenous TCF3-HLF and dissect its essential transcriptional components and targets by functional genomics. We demonstrate that TCF3-HLF recruits HLF binding sites at hematopoietic stem cell/myeloid lineage associated (super-) enhancers to drive lineage identity and self-renewal. Among direct targets, hijacking an HLF binding site in a MYC enhancer cluster by TCF3-HLF activates a conserved MYC-driven transformation program crucial for leukemia propagation in vivo. TCF3-HLF pioneers the cooperation with ERG and recruits histone acetyltransferase p300 (EP300), conferring susceptibility to EP300 inhibition. Our study provides a framework for targeting driving transcriptional dependencies in this fatal leukemia.

Keywords: BRD4; EP300; ERG; MYC; TCF3-HLF; chimeric transcription factor; drug resistance; enhancer; leukemia; topologically associating domain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic-Leucine Zipper Transcription Factors / genetics
  • DNA-Binding Proteins / genetics
  • E1A-Associated p300 Protein / genetics*
  • Humans
  • Oncogene Proteins, Fusion / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Translocation, Genetic


  • Basic-Leucine Zipper Transcription Factors
  • DNA-Binding Proteins
  • Oncogene Proteins, Fusion
  • TCF3-HLF fusion protein, human
  • E1A-Associated p300 Protein
  • EP300 protein, human