Ewing sarcoma (EwS) is associated with poor prognosis despite current multimodal therapy. Targeting of EWS-FLI1, the fusion protein responsible for its pathogenesis, and its principal downstream targets has not yet produced satisfactory therapeutic options, fueling the search for alternative approaches. Here, we show that the oncofetal RNA-binding protein LIN28B regulates the stability of EWS-FLI1 mRNA in ~10% of EwSs. LIN28B depletion in these tumors leads to a decrease in the expression of EWS-FLI1 and its direct transcriptional network, abrogating EwS cell self-renewal and tumorigenicity. Moreover, pharmacological inhibition of LIN28B mimics the effect of LIN28B depletion, suggesting that LIN28B sustains the emergence of a subset of EwS in which it also serves as an effective therapeutic target.

尽管目前采用多模式疗法，但尤文氏肉瘤（EwS）与不良预后相关。靶向EWS-FLI1（负责其发病机理的融合蛋白）及其主要下游靶点尚未产生令人满意的治疗选择，这为寻找替代方法提供了动力。在这里，我们显示了胎粪RNA结合蛋白LIN28B在约10％的EwSs中调节EWS-FLI1 mRNA的稳定性。这些肿瘤中的LIN28B耗竭导致EWS-FLI1及其直接转录网络的表达减少，从而废除了EwS细胞的自我更新和致瘤性。此外，LIN28B的药理学抑制作用模拟了LIN28B耗竭的效果，这表明LIN28B维持了一部分EwS的出现，在其中它也充当了有效的治疗靶标。