LIN28B underlies the pathogenesis and therapeutic sensitivity of a subclass of Ewing sarcoma

Ewing sarcoma (EwS) is a pediatric bone malignancy associated with high mortality despite aggressive multimodal therapy. Targeting EWS-FLI-1, the fusion protein responsible for EwS pathogenesis, or its principal downstream target gene products have not produced effective therapeutic options, fuelling the quest for alternative approaches. Here, we show that the oncofoetal RNA-binding protein Lin28B is expressed in a subset of EwS in which it directly binds and safeguards EWS-FLI-1 transcripts. Depletion and pharmacologic inhibition of Lin28B in primary patient-derived EwS cultures led not only to a decrease in EWS-FLI-1 expression but also to the deconstruction of its direct transcriptional network, abrogating EwS cell self-renewal and tumorigenicity. Our observations demonstrate that Lin28B provides indispensable support for EWS-FLI-1 to sustain the emergence of a EwS subset in which it also constitutes a promising therapeutic target. Four samples of spherogenic cultures from primary Ewing sarcomas, plus six samples of the same after various shRNA, overexpression and drug treatments