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: ER-Hoxb8 cells stably expressing ERG variants and an empty vector for control were carefully washed to remove beta-estradiol followed by treatment with either 5µM BRD3308 or DMSO. For each sample type, we conducted four independent experiments. Cells were incubated for 36 hours, fluidized in TRIzol, and prepared for RNA sequencing