SF3B1

Nature Genetics (2023)Cite this article

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Across multiple cancer types, hotspot mutations in SF3B1 confer selective sensitivity to multiple clinically available PARP inhibitors. This sensitivity is due to reduced levels of CINP specifically in SF3B1-mutant cells, which leads to a loss of the canonical replication stress response after challenge with PARP inhibitors.

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Yoshimi, D. & Abdel-Wahab, O. Molecular pathways: understanding and targeting mutant spliceosomal proteins. Clin. Cancer Res. 23, 336–341 (2017). This review discusses the role of mutations in spliceosomal component proteins.

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Alsafadi, S. et al. Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage. Nat. Commun. 7, 10615 (2016). This is one of the first reports describing the mis-splicing events in SF3B1MUT cancers and the mechanism behind this.

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Liu, Z. et al. Mutations in the RNA splicing factor SF3B1 promote tumorigenesis through MYC stabilization. Cancer Discov. 10, 806–821 (2020). This paper reports that SF3B1MUT cancers show hyperactivation of the proto-oncoprotein MYC that promotes tumor growth.

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Inoue, D. et al. Spliceosomal disruption of the non-canonical BAF complex in cancer. Nature 574, 432–436 (2019). This paper shows that mis-splicing of the chromatin-remodeling protein BRD9 drives tumorigenesis in SF3B1MUT cancers and can be rescued through morpholino delivery.

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Pratt, G. et al. A multi-centre phase I trial of the PARP inhibitor olaparib in patients with relapsed chronic lymphocytic leukaemia, T-prolymphocytic leukaemia or mantle cell lymphoma. Br. J. Haematol. 182, 429–433 (2018). This paper reports a phase 1 clinical trial of olaparib in treatment-refractory leukemias; this is the only clinical trial of a PARP inhibitor in patients with known SF3B1 mutations.

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This is a summary of: Bland, P. et al. SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response. Nat. Genet. https://doi.org/10.1038/s41588-023-01460-5 (2023).

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SF3B1-mutant cells succumb to replication stress under PARP inhibition. Nat Genet (2023). https://doi.org/10.1038/s41588-023-01461-4

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Published: 01 August 2023

DOI: https://doi.org/10.1038/s41588-023-01461-4

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