Mechanisms of ETV6/RUNX1-mediated gene regulation in leukemia

The t(12;21)(p13;q22) chromosomal translocation, which generates the ETV6/RUNX1 (E/R) fusion gene, is present in about 20% of childhood acute lymphoblastic leukemia (ALL). It leads to a chimeric transcription factor consisting of the N-terminal region of ETV6 and almost the entire RUNX1 protein. E/R is under the transcriptional control of the ETV6 promoter and regulates transcription via the DNA-binding RUNT homology domain of RUNX1. So far, experimental evidence suggested that E/R acts as a constitutive repressor of RUNX1 target genes by aberrantly recruiting transcriptional repressors. This notion, however, has been challenged by recent publications, which include findings of our group (Fuka et al., PlosOne 2011), showing that E/R also up-regulates RUNX1 target genes. These findings suggest a more complex orchestration of E/R target gene regulation than previously assumed.

To shed light on the various mechanisms of genome-wide E/R target gene regulation in leukemia, we are currently establishing a conditional E/R-expression system in a leukemic model cell line that will be used for comprehensive and integrative analyses of DNA binding and gene regulation, the identification of affected pathways and also of transcription factors that co-operate with E/R on target gene promoters. In this talk the outline and current state of the project will be presented.