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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE122632 | GEO | 2020/04/30

REPOSITORIES: GEO

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LIN28B underlies the pathogenesis of a subclass of Ewing sarcoma

Project description:Ewing sarcoma (EwS) is associated with poor prognosis despite current multimodal therapy. Targeting of EWS-FLI-1, the fusion protein responsible for its pathogenesis, and its principal downstream targets has not yet produced satisfactory therapeutic options, fuelling the search for alternative approaches. Here, we show that the oncofoetal RNA-binding protein Lin28B regulates the stability of EWS-FLI-1 mRNA in about 10% of EwS. Lin28B depletion in these tumours leads to a decrease in expression of EWS-FLI-1 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.

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