Oral Presentation 16th Asian Conference on Transcription 2019

Mechanism of E2A-PBX1-mediated transcription in acute lymphoblastic leukemia (1167)

Wei-Yi Chen 1
  1. National Yang-Ming University, Taipei, TAIWAN, Taiwan

The dimeric E2A, which acts in concert with other lineage-specific factors, plays an important role in the development of B- and T- lymphocytes, and is also of significance for certain pediatric leukemias. In this regard, genetic lesions generate E2A-fusion proteins (E2A-PBX1 and E2A-HLF) with novel biochemical properties, including binding to distinct DNA sequences, and functional activities that contribute to tumor formation. Numerous studies have established the oncogenic functions of these two fusion proteins in cell and animal models, as well as biochemical properties in vitro. However, the E2A-fusion-enforced cistrome and related mechanisms underlying leukemogenesis in human acute lymphoblastic leukemia cells remain far from clear.

In current study, we determined the unbiased genome-wide binding and transcription signatures of the oncogenic E2A-PBX1 in human pre-B ALL-derived cell lines. Our results demonstrate that E2A-PBX1 preferentially binds to a subset of RUNX1-occupied enhancers through a direct interaction with DNA-bound RUNX1 – and not through the PBX1 DNA-binding homeodomain as had been proposed. In addition, we also show that enrichments of p300, MED1/Mediator and K27 acetylated histone H3 activation signals are a feature of E2A-PBX1-targeted RUNX1 sites that could promote the enhanced expression of associated genes. Importantly, we find that E2A-PBX1 not only binds to RUNX1-controlled genes, but also targets the positive feedback loop of the RUNX1 locus. Hence, the positive impact of E2A-PBX1 on activation of the RUNX1 locus and downstream RUNX1 targets may contribute to a sustained RUNX1 transcriptome in pre-B cells that leads to leukemogenesis.