The NCOR-HDAC3 co-repressive complex modulates the leukemogenic potential of ERG.

The ETS transcription factor ERG is involved in several cancers including leukemia. However, ERG domains and co-factors involved in leukemogenesis remain largely uncharacterized and as a transcription factor it is currently undruggable. Here, we report a critical role for the conserved amino-acid proline at position 199, at the 3' end of the PNT domain, for ERG's leukemogenic activity. Specifically, we demonstrate that it is required for ERG-induced self-renewal and restriction of myeloid differentiation in hematopoietic progenitor cells and for initiation of leukemia in mouse transduction/transplantation models. Mechanistically, we show that P199 facilitates the interaction of ERG with the NCoR-HDAC3 co-repressor complex. Inhibition of HDAC3 reduced in vitro and in vivo growth of human ERG-dependent leukemic cells as well as growth of ERG dependent prostate cancer cells. Thus, the interaction of ERG with the NCoR-HDAC3 co-repressor complex is required for its oncogenic activity and modulation of this interaction may provide an opportunity for therapeutic intervention. Overall design: ChIP material was prepared from ER-Hoxb8 cells stably expressing ERG variants and an empty vector for control. Immunoprecipitation was preform using polyclonal antibody raised against H3K27ac, H3K4me1, H3K4me3, H3K9ac (Abcam). As a control, nonspecific rabbit IgG (I5006; Sigma Aldrich) was used.