ERG-driven prostate cancer initiation is cell-context dependent and requires KMT2A and DOT1L

Despite the high prevalence of ERG transcription factor translocations in prostate cancer, the mechanism of tumorigenicity remains poorly understood. Using lineage tracing, we find the tumor-initiating activity of ERG resides in a subpopulation of murine basal cells that coexpress luminal genes (Basal^Lum) and not in the larger population of ERG⁺ luminal cells. Upon ERG activation, Basal^Lum cells give rise to highly proliferative intermediate (IM) cells with stem-like features that coexpress basal, luminal, hillock and club marker genes, before transitioning to Krt8⁺ luminal cells. Transcriptomic analysis of ERG⁺ human prostate cancers confirms the presence of rare ERG⁺ Basal^Lum cells, as well as IM cells whose presence is associated with a worse prognosis. Single-cell analysis revealed a chromatin state in ERG⁺ IM cells enriched for STAT3 transcription factor binding sites and elevated expression of the KMT2A/MLL1 and DOT1L, all three of which are essential for ERG-driven tumorigenicity in vivo. In addition to providing translational opportunities, this work illustrates how single-cell approaches combined with lineage tracing can identify cancer vulnerabilities not evident from bulk analysis.