The ERG (ETS-related gene) transcription factor is linked to various types of cancer, including leukemia. However, the specific ERG domains and co-factors contributing to leukemogenesis are poorly understood. Drug targeting a transcription factor such as ERG is challenging. Our study reveals the critical role of a conserved amino acid, proline, at position 199, located at the 3’ end of the PNT (pointed) domain, in ERG’s ability to induce leukemia. P199 is necessary for ERG to promote self-renewal, prevent myeloid differentiation in hematopoietic progenitor cells, and initiate leukemia in mouse models. Here we show that P199 facilitates ERG’s interaction with the NCoR-HDAC3 co-repressor complex. Inhibiting HDAC3 reduces the growth of ERG-dependent leukemic and prostate cancer cells, indicating that the interaction between ERG and the NCoR-HDAC3 co-repressor complex is crucial for its oncogenic activity. Thus, targeting this interaction may offer a potential therapeutic intervention.

ERG（ETS 相关基因）转录因子与多种类型的癌症有关，包括白血病。然而，人们对导致白血病发生的特定 ERG 结构域和辅助因子知之甚少。针对 ERG 等转录因子的药物具有挑战性。我们的研究揭示了位于 PNT（尖头）结构域 3' 端 199 位的保守氨基酸脯氨酸在 ERG 诱导白血病能力中的关键作用。P199 对于 ERG 促进自我更新、防止造血祖细胞中的骨髓分化以及引发小鼠模型中的白血病而言是必需的。在这里，我们表明 P199 促进 ERG 与 NCoR-HDAC3 共阻遏物复合物的相互作用。抑制 HDAC3 可减少 ERG 依赖性白血病和前列腺癌细胞的生长，表明 ERG 与 NCoR-HDAC3 共阻遏物复合物之间的相互作用对其致癌活性至关重要。因此，针对这种相互作用可能提供潜在的治疗干预。