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The ETS transcription factor ERG is involved in several cancers including leukemias. We and others have demonstrated a direct role for ERG in leukemia initiation and maintenance of several subtypes of myeloid and lymphoid leukemias. However, ERG domains and co-factors involved in leukemogenesis remains largely uncharacterized and as a transcription factor it is 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 reverses ERG’s restriction of myeloid differentiation and reduces human ERG-dependent leukemic burden in immunodeficient mice. 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.