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RNA splicing dysregulation and the hallmarks of cancer

Abstract

Dysregulated RNA splicing is a molecular feature that characterizes almost all tumour types. Cancer-associated splicing alterations arise from both recurrent mutations and altered expression of trans-acting factors governing splicing catalysis and regulation. Cancer-associated splicing dysregulation can promote tumorigenesis via diverse mechanisms, contributing to increased cell proliferation, decreased apoptosis, enhanced migration and metastatic potential, resistance to chemotherapy and evasion of immune surveillance. Recent studies have identified specific cancer-associated isoforms that play critical roles in cancer cell transformation and growth and demonstrated the therapeutic benefits of correcting or otherwise antagonizing such cancer-associated mRNA isoforms. Clinical-grade small molecules that modulate or inhibit RNA splicing have similarly been developed as promising anticancer therapeutics. Here, we review splicing alterations characteristic of cancer cell transcriptomes, dysregulated splicing’s contributions to tumour initiation and progression, and existing and emerging approaches for targeting splicing for cancer therapy. Finally, we discuss the outstanding questions and challenges that must be addressed to translate these findings into the clinic.

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Fig. 1: Principles of constitutive and alternative splicing.
Fig. 2: Recurrent splicing factor alterations in cancer.
Fig. 3: Splicing hallmarks of cancer.
Fig. 4: Splicing-driven alterations in drug responses.
Fig. 5: Therapeutic approaches to target splicing in cancer.

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References

  1. Black, D. L. Mechanisms of alternative pre-messenger RNA splicing. Annu. Rev. Biochem. 72, 291–336 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Reixachs-Sole, M. & Eyras, E. Uncovering the impacts of alternative splicing on the proteome with current omics techniques. Wiley Interdiscip. Rev. RNA 13, e1707 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Blencowe, B. J. Alternative splicing: new insights from global analyses. Cell 126, 37–47 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Wang, E. T. et al. Alternative isoform regulation in human tissue transcriptomes. Nature 456, 470–476 (2008). This landmark study uses RNA-seq to quantify isoform expression across tissues.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kahles, A. et al. Comprehensive analysis of alternative splicing across tumors from 8705 patients. Cancer Cell 34, 211–224.e6 (2018). This landmark study identifies splicing alterations across tumour types.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Urbanski, L. M., Leclair, N. & Anczukow, O. Alternative-splicing defects in cancer: splicing regulators and their downstream targets, guiding the way to novel cancer therapeutics. Wiley Interdiscip. Rev. RNA 9, 1476 (2018).

    Article  Google Scholar 

  7. Dvinge, H., Kim, E., Abdel-Wahab, O. & Bradley, R. K. RNA splicing factors as oncoproteins and tumour suppressors. Nat. Rev. Cancer 16, 413–430 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Stanley, R. F. & Abdel-Wahab, O. Dysregulation and therapeutic targeting of RNA splicing in cancer. Nat. Cancer 3, 536–546 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bonnal, S. C., López-Oreja, I. & Valcárcel, J. Roles and mechanisms of alternative splicing in cancer—implications for care. Nat. Rev. Clin. Oncol. 17, 457–474 (2020).

    Article  PubMed  Google Scholar 

  10. Hanahan, D. Hallmarks of cancer: new dimensions. Cancer Discov. 12, 31–46 (2022).

    Article  CAS  PubMed  Google Scholar 

  11. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Wilkinson, M. E., Charenton, C. & Nagai, K. RNA splicing by the spliceosome. Annu. Rev. Biochem. 89, 359–388 (2020).

    Article  CAS  PubMed  Google Scholar 

  13. Akinyi, M. V. & Frilander, M. J. At the intersection of major and minor spliceosomes: crosstalk mechanisms and their impact on gene expression. Front. Genet. 12, 700744 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lee, Y. & Rio, D. C. Mechanisms and regulation of alternative pre-mRNA splicing. Annu. Rev. Biochem. 84, 291–323 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ellis, J. D. et al. Tissue-specific alternative splicing remodels protein–protein interaction networks. Mol. Cell 46, 884–892 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Tung, K. F., Pan, C. Y., Chen, C. H. & Lin, W. C. Top-ranked expressed gene transcripts of human protein-coding genes investigated with GTEx dataset. Sci. Rep. 10, 16245 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Howard, J. M. & Sanford, J. R. The RNAissance family: SR proteins as multifaceted regulators of gene expression. Wiley Interdiscip. Rev. RNA 6, 93–110 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. Geuens, T., Bouhy, D. & Timmerman, V. The hnRNP family: insights into their role in health and disease. Hum. Genet. 135, 851–867 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Papaemmanuil, E. et al. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N. Engl. J. Med. 365, 1384–1395 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yoshida, K. et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 478, 64–69 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Harbour, J. W. et al. Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma. Nat. Genet. 45, 133–135 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Martin, M. et al. Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3. Nat. Genet. 45, 933–936 (2013). Together with Harbour et al. (2013), this paper identifies recurrent mutations in SF3B1 in UVM.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Imielinski, M. et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150, 1107–1120 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lee, S. C. et al. Synthetic lethal and convergent biological effects of cancer-associated spliceosomal gene mutations. Cancer Cell 34, 225–241.e8 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Taylor, J. et al. Single-cell genomics reveals the genetic and molecular bases for escape from mutational epistasis in myeloid neoplasms. Blood 136, 1477–1486 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Wang, L. et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N. Engl. J. Med. 365, 2497–2506 (2011). This work identifies recurrent mutations in SF3B1 in CLL.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Alsafadi, S. et al. Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage. Nat. Commun. 7, 10615 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Darman, R. B. et al. Cancer-associated SF3B1 hotspot mutations induce cryptic 3′ splice site selection through use of a different branch point. Cell Rep. 13, 1033–1045 (2015). This work demonstrates that recurrent SF3B1 mutations alter branch point selection.

    Article  CAS  PubMed  Google Scholar 

  29. Dalton, W. B. et al. The K666N mutation in SF3B1 is associated with increased progression of MDS and distinct RNA splicing. Blood Adv. 4, 1192–1196 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Inoue, D. et al. Spliceosomal disruption of the non-canonical BAF complex in cancer. Nature 574, 432–436 (2019). This work shows that SF3B1 mutations disrupt chromatin remodelling to promote tumorigenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lieu, Y. K. et al. SF3B1 mutant-induced missplicing of MAP3K7 causes anemia in myelodysplastic syndromes. Proc. Natl Acad. Sci. USA 119, 2111703119 (2022).

    Article  Google Scholar 

  32. Clough, C. A. et al. Coordinated missplicing of TMEM14C and ABCB7 causes ring sideroblast formation in SF3B1-mutant myelodysplastic syndrome. Blood 139, 2038–2049 (2022).

    Article  CAS  PubMed  Google Scholar 

  33. Yoshimi, A. et al. Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis. Nature 574, 273–277 (2019). This work demonstrates genetic and functional interactions between SRSF2 and IDH2 in leukaemia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Robertson, A. G. et al. Integrative analysis identifies four molecular and clinical subsets in uveal melanoma. Cancer Cell 32, 204–220.e15 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kim, E. et al. SRSF2 mutations contribute to myelodysplasia by mutant-specific effects on exon recognition. Cancer Cell 27, 617–630 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gallardo, M. et al. hnRNP K is a haploinsufficient tumor suppressor that regulates proliferation and differentiation programs in hematologic malignancies. Cancer Cell 28, 486–499 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Graubert, T. A. et al. Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nat. Genet. 44, 53–57 (2012).

    Article  CAS  Google Scholar 

  38. Brooks, A. N. et al. A pan-cancer analysis of transcriptome changes associated with somatic mutations in U2AF1 reveals commonly altered splicing events. PLoS ONE 9, 87361 (2014).

    Article  Google Scholar 

  39. Ilagan, J. O. et al. U2AF1 mutations alter splice site recognition in hematological malignancies. Genome Res. 25, 14–26 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Smith, M. A. et al. U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies. Nat. Cell Biol. 21, 640–650 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Biancon, G. et al. Precision analysis of mutant U2AF1 activity reveals deployment of stress granules in myeloid malignancies. Mol. Cell 82, 1107–1122.e7 (2022).

    Article  CAS  PubMed  Google Scholar 

  42. Damm, F. et al. Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes. Blood 119, 3211–3218 (2012).

    Article  CAS  PubMed  Google Scholar 

  43. Haferlach, T. et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia 28, 241–247 (2014).

    Article  CAS  PubMed  Google Scholar 

  44. Madan, V. et al. Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome. Nat. Commun. 6, 6042 (2015).

    Article  CAS  PubMed  Google Scholar 

  45. Inoue, D. et al. Minor intron retention drives clonal hematopoietic disorders and diverse cancer predisposition. Nat. Genet. 53, 707–718 (2021). This work shows that disruption of minor intron splicing by ZRSR2 mutations promotes clonal advantage.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang, X., Song, X. & Yan, X. Effect of RNA splicing machinery gene mutations on prognosis of patients with MDS: a meta-analysis. Medicine 98, e15743 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Obeng, E. A. et al. Physiologic expression of Sf3b1K700E causes impaired erythropoiesis, aberrant splicing, and sensitivity to therapeutic spliceosome modulation. Cancer Cell 30, 404–417 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Shirai, C. L. et al. Mutant U2AF1 expression alters hematopoiesis and pre-mRNA splicing in vivo. Cancer Cell 27, 631–643 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Fei, D. L. et al. Impaired hematopoiesis and leukemia development in mice with a conditional knock-in allele of a mutant splicing factor gene U2af1. Proc. Natl Acad. Sci. USA 115, 10437–E10446 (2018).

    Article  Google Scholar 

  50. Mian, S. A. et al. SF3B1 mutant MDS-initiating cells may arise from the haematopoietic stem cell compartment. Nat. Commun. 6, 10004 (2015). This work shows that SF3B1 mutations are initiating events in MDS.

    Article  CAS  PubMed  Google Scholar 

  51. Fabre, M. A. et al. The longitudinal dynamics and natural history of clonal haematopoiesis. Nature 606, 335–342 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).

    Article  Google Scholar 

  53. Ibrahimpasic, T. et al. Genomic alterations in fatal forms of non-anaplastic thyroid cancer: identification of MED12 and RBM10 as novel thyroid cancer genes associated with tumor virulence. Clin. Cancer Res. 23, 5970–5980 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Anczuków, O. & Krainer, A. R. Splicing-factor alterations in cancers. RNA 22, 1285–1301 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Seiler, M. et al. Somatic mutational landscape of splicing factor genes and their functional consequences across 33 cancer types. Cell Rep. 23, 282–296.e4 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Escobar-Hoyos, L. F. et al. Altered RNA splicing by mutant p53 activates oncogenic RAS signaling in pancreatic cancer. Cancer Cell 38, 198–211.e8 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Anczukow, O. et al. The splicing factor SRSF1 regulates apoptosis and proliferation to promote mammary epithelial cell transformation. Nat. Struct. Mol. Biol. 19, 220–228 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Anczukow, O. et al. SRSF1-regulated alternative splicing in breast cancer. Mol. Cell 60, 105–117 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Park, S. et al. Differential functions of splicing factors in mammary transformation and breast cancer metastasis. Cell Rep. 29, 2672–2688.e7 (2019). This work identifies the functional roles of individual SR proteins in breast cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Karni, R. et al. The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat. Struct. Mol. Biol. 14, 185–193 (2007). This landmark study shows that SRSF1 is a proto-oncoprotein.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sebestyén, E. et al. Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks. Genome Res. 26, 732–744 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Ghigna, C. et al. Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene. Mol. Cell 20, 881–890 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Das, S., Anczukow, O., Akerman, M. & Krainer, A. R. Oncogenic splicing factor SRSF1 is a critical transcriptional target of MYC. Cell Rep. 1, 110–117 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. De Miguel, F. J. et al. Identification of alternative splicing events regulated by the oncogenic factor SRSF1 in lung cancer. Cancer Res. 74, 1105–1115 (2014).

    Article  PubMed  Google Scholar 

  65. Michlewski, G., Sanford, J. R. & Caceres, J. F. The splicing factor SF2/ASF regulates translation initiation by enhancing phosphorylation of 4E-BP1. Mol. Cell 30, 179–189 (2008).

    Article  CAS  PubMed  Google Scholar 

  66. Karni, R., Hippo, Y., Lowe, S. W. & Krainer, A. R. The splicing-factor oncoprotein SF2/ASF activates mTORC1. Proc. Natl Acad. Sci. USA 105, 15323–15327 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Sen, S., Langiewicz, M., Jumaa, H. & Webster, N. J. Deletion of serine/arginine-rich splicing factor 3 in hepatocytes predisposes to hepatocellular carcinoma in mice. Hepatology 61, 171–183 (2015).

    Article  CAS  PubMed  Google Scholar 

  68. Ajiro, M., Jia, R., Yang, Y., Zhu, J. & Zheng, Z. M. A genome landscape of SRSF3-regulated splicing events and gene expression in human osteosarcoma U2OS cells. Nucleic Acids Res. 44, 1854–1870 (2016).

    Article  PubMed  Google Scholar 

  69. Wang, Z. et al. Exon-centric regulation of pyruvate kinase M alternative splicing via mutually exclusive exons. J. Mol. Cell Biol. 4, 79–87 (2012).

    Article  CAS  PubMed  Google Scholar 

  70. Kurokawa, K. et al. Downregulation of serine/arginine-rich splicing factor 3 induces G1 cell cycle arrest and apoptosis in colon cancer cells. Oncogene 33, 1407–1417 (2014).

    Article  CAS  PubMed  Google Scholar 

  71. Jia, R., Ajiro, M., Yu, L., McCoy, P. Jr & Zheng, Z. M. Oncogenic splicing factor SRSF3 regulates ILF3 alternative splicing to promote cancer cell proliferation and transformation. RNA 25, 630–644 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Freytag, M. et al. Epithelial splicing regulatory protein 1 and 2 (ESRP1 and ESRP2) upregulation predicts poor prognosis in prostate cancer. BMC Cancer 20, 1220 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Gokmen-Polar, Y. et al. Splicing factor ESRP1 controls ER-positive breast cancer by altering metabolic pathways. EMBO Rep. 20, 46078 (2019).

    Article  Google Scholar 

  74. Shapiro, I. M. et al. An EMT-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype. PLoS Genet. 7, 1002218 (2011).

    Article  Google Scholar 

  75. Munkley, J. et al. Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer. eLife 8, 47678 (2019).

    Article  Google Scholar 

  76. Ishii, H. et al. Epithelial splicing regulatory proteins 1 (ESRP1) and 2 (ESRP2) suppress cancer cell motility via different mechanisms. J. Biol. Chem. 289, 27386–27399 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bechara, E. G., Sebestyen, E., Bernardis, I., Eyras, E. & Valcarcel, J. RBM5, 6, and 10 differentially regulate NUMB alternative splicing to control cancer cell proliferation. Mol. Cell 52, 720–733 (2013). This work demonstrates the role of RBMs in tumorigenesis.

    Article  CAS  PubMed  Google Scholar 

  78. Rintala-Maki, N. D. et al. Expression of RBM5-related factors in primary breast tissue. J. Cell Biochem. 100, 1440–1458 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. Inoue, A. RBM10: structure, functions, and associated diseases. Gene 783, 145463 (2021).

    Article  CAS  PubMed  Google Scholar 

  80. Lu, W. et al. QKI impairs self-renewal and tumorigenicity of oral cancer cells via repression of SOX2. Cancer Biol. Ther. 15, 1174–1184 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Zong, F. Y. et al. The RNA-binding protein QKI suppresses cancer-associated aberrant splicing. PLoS Genet. 10, 1004289 (2014).

    Article  Google Scholar 

  82. Bandopadhayay, P. et al. MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat. Genet. 48, 273–282 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Shirakihara, T. et al. TGF-β regulates isoform switching of FGF receptors and epithelial–mesenchymal transition. EMBO J. 30, 783–795 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Warzecha, C. C. et al. An ESRP-regulated splicing programme is abrogated during the epithelial–mesenchymal transition. EMBO J. 29, 3286–3300 (2010). This work demonstrates the important role played by regulated splicing during EMT.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Warzecha, C. C., Shen, S., Xing, Y. & Carstens, R. P. The epithelial splicing factors ESRP1 and ESRP2 positively and negatively regulate diverse types of alternative splicing events. RNA Biol. 6, 546–562 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Yae, T. et al. Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell. Nat. Commun. 3, 883 (2012). This work demonstrates the role of a CD44 isoform in lung metastasis in vivo.

    Article  PubMed  Google Scholar 

  87. Sutherland, L. C., Wang, K. & Robinson, A. G. RBM5 as a putative tumor suppressor gene for lung cancer. J. Thorac. Oncol. 5, 294–298 (2010).

    Article  PubMed  Google Scholar 

  88. Jamsai, D. et al. In vivo evidence that RBM5 is a tumour suppressor in the lung. Sci. Rep. 7, 16323 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Zhao, Y. et al. The tumor suppressing effects of QKI-5 in prostate cancer: a novel diagnostic and prognostic protein. Cancer Biol. Ther. 15, 108–118 (2014).

    Article  CAS  PubMed  Google Scholar 

  90. Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015).

    Article  CAS  PubMed  Google Scholar 

  91. Jung, H. et al. Intron retention is a widespread mechanism of tumor-suppressor inactivation. Nat. Genet. 47, 1242–1248 (2015).

    Article  CAS  PubMed  Google Scholar 

  92. Mogilevsky, M. et al. Modulation of MKNK2 alternative splicing by splice-switching oligonucleotides as a novel approach for glioblastoma treatment. Nucleic Acids Res. 46, 11396–11404 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Koh, C. M. et al. MYC regulates the core pre-mRNA splicing machinery as an essential step in lymphomagenesis. Nature 523, 96–100 (2015). This work identifies a MYC-driven splicing vulnerability.

    Article  CAS  PubMed  Google Scholar 

  94. Ben-Hur, V. et al. S6K1 alternative splicing modulates its oncogenic activity and regulates mTORC1. Cell Rep. 3, 103–115 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. Amaral, C. L. et al. S6Ks isoforms contribute to viability, migration, docetaxel resistance and tumor formation of prostate cancer cells. BMC Cancer 16, 602 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Mei, H., Wang, Y., Fan, J. & Lin, Z. Alternative splicing of S6K1 promotes non-small cell lung cancer survival. Tumour Biol. 37, 13369–13376 (2016).

    Article  CAS  PubMed  Google Scholar 

  97. David, C. J., Chen, M., Assanah, M., Canoll, P. & Manley, J. L. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 463, 364–368 (2010).

    Article  CAS  PubMed  Google Scholar 

  98. Clower, C. V. et al. The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism. Proc. Natl Acad. Sci. USA 107, 1894–1899 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Dayton, T. L., Jacks, T. & Vander Heiden, M. G. PKM2, cancer metabolism, and the road ahead. EMBO Rep. 17, 1721–1730 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Wang, Z., Jeon, H. Y., Rigo, F., Bennett, C. F. & Krainer, A. R. Manipulation of PK-M mutually exclusive alternative splicing by antisense oligonucleotides. Open. Biol. 2, 120133 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Boise, L. H. et al. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74, 597–608 (1993).

    Article  CAS  PubMed  Google Scholar 

  102. Wu, L., Mao, C. & Ming, X. Modulation of Bcl-x alternative splicing induces apoptosis of human hepatic stellate cells. Biomed. Res. Int. 2016, 7478650 (2016).

    PubMed  PubMed Central  Google Scholar 

  103. Dole, M. G. et al. Bcl-xS enhances adenoviral vector-induced apoptosis in neuroblastoma cells. Cancer Res. 56, 5734–5740 (1996).

    CAS  PubMed  Google Scholar 

  104. Minn, A. J., Boise, L. H. & Thompson, C. B. Bcl-x(S) anatagonizes the protective effects of Bcl-x(L). J. Biol. Chem. 271, 6306–6312 (1996).

    Article  CAS  PubMed  Google Scholar 

  105. Paronetto, M. P., Achsel, T., Massiello, A., Chalfant, C. E. & Sette, C. The RNA-binding protein Sam68 modulates the alternative splicing of Bcl-x. J. Cell Biol. 176, 929–939 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Zhou, A., Ou, A. C., Cho, A., Benz, E. J. Jr & Huang, S. C. Novel splicing factor RBM25 modulates Bcl-x pre-mRNA 5′ splice site selection. Mol. Cell Biol. 28, 5924–5936 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Bielli, P., Bordi, M., Di Biasio, V. & Sette, C. Regulation of BCL-X splicing reveals a role for the polypyrimidine tract binding protein (PTBP1/hnRNP I) in alternative 5′ splice site selection. Nucleic Acids Res. 42, 12070–12081 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Wang, Y. et al. The splicing factor RBM4 controls apoptosis, proliferation, and migration to suppress tumor progression. Cancer Cell 26, 374–389 (2014). This work demonstrates the role of RBMs in tumorigenesis in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Moore, M. J., Wang, Q., Kennedy, C. J. & Silver, P. A. An alternative splicing network links cell-cycle control to apoptosis. Cell 142, 625–636 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Garneau, D., Revil, T., Fisette, J. F. & Chabot, B. Heterogeneous nuclear ribonucleoprotein F/H proteins modulate the alternative splicing of the apoptotic mediator Bcl-x. J. Biol. Chem. 280, 22641–22650 (2005).

    Article  CAS  PubMed  Google Scholar 

  111. Revil, T., Pelletier, J., Toutant, J., Cloutier, A. & Chabot, B. Heterogeneous nuclear ribonucleoprotein K represses the production of pro-apoptotic Bcl-xS splice isoform. J. Biol. Chem. 284, 21458–21467 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Cloutier, P. et al. Antagonistic effects of the SRp30c protein and cryptic 5′ splice sites on the alternative splicing of the apoptotic regulator Bcl-x. J. Biol. Chem. 283, 21315–21324 (2008).

    Article  CAS  PubMed  Google Scholar 

  113. Pabla, N., Bhatt, K. & Dong, Z. Checkpoint kinase 1 (Chk1)-short is a splice variant and endogenous inhibitor of Chk1 that regulates cell cycle and DNA damage checkpoints. Proc. Natl Acad. Sci. USA 109, 197–202 (2012).

    Article  CAS  PubMed  Google Scholar 

  114. Hu, G. et al. Clinical and functional significance of CHK1-S, an alternatively spliced isoform of the CHK1 gene, in hepatocellular carcinoma. J. Cancer 11, 1792–1799 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Wong, M. S., Shay, J. W. & Wright, W. E. Regulation of human telomerase splicing by RNA:RNA pairing. Nat. Commun. 5, 3306 (2014).

    Article  PubMed  Google Scholar 

  116. Sayed, M. E. et al. NOVA1 directs PTBP1 to hTERT pre-mRNA and promotes telomerase activity in cancer cells. Oncogene 38, 2937–2952 (2019).

    Article  CAS  PubMed  Google Scholar 

  117. Ludlow, A. T. et al. NOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer. Nat. Commun. 9, 3112 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Listerman, I., Sun, J., Gazzaniga, F. S., Lukas, J. L. & Blackburn, E. H. The major reverse transcriptase-incompetent splice variant of the human telomerase protein inhibits telomerase activity but protects from apoptosis. Cancer Res. 73, 2817–2828 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Pont, A. R., Sadri, N., Hsiao, S. J., Smith, S. & Schneider, R. J. mRNA decay factor AUF1 maintains normal aging, telomere maintenance, and suppression of senescence by activation of telomerase transcription. Mol. Cell 47, 5–15 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Kang, X., Chen, W., Kim, R. H., Kang, M. K. & Park, N. H. Regulation of the hTERT promoter activity by MSH2, the hnRNPs K and D, and GRHL2 in human oral squamous cell carcinoma cells. Oncogene 28, 565–574 (2009).

    Article  CAS  PubMed  Google Scholar 

  121. DiFeo, A., Martignetti, J. A. & Narla, G. The role of KLF6 and its splice variants in cancer therapy. Drug. Resist. Updat. 12, 1–7 (2009).

    Article  CAS  PubMed  Google Scholar 

  122. Hatami, R. et al. KLF6-SV1 drives breast cancer metastasis and is associated with poor survival. Sci. Transl. Med. 5, 12 (2013).

    Article  Google Scholar 

  123. Yea, S. et al. Ras promotes growth by alternative splicing-mediated inactivation of the KLF6 tumor suppressor in hepatocellular carcinoma. Gastroenterology 134, 1521–1531 (2008).

    Article  CAS  PubMed  Google Scholar 

  124. Botella, L. M. et al. TGF-β regulates the expression of transcription factor KLF6 and its splice variants and promotes co-operative transactivation of common target genes through a Smad3–Sp1–KLF6 interaction. Biochem. J. 419, 485–495 (2009).

    Article  CAS  PubMed  Google Scholar 

  125. DiFeo, A. et al. A functional role for KLF6–SV1 in lung adenocarcinoma prognosis and chemotherapy response. Cancer Res. 68, 965–970 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Tanaka, N., Yoshida, H., Suzuki, Y. & Harigaya, K. Relative expression of hMena11a and hMenaINV splice isoforms is a useful biomarker in development and progression of human breast carcinoma. Int. J. Oncol. 45, 1921–1928 (2014).

    Article  CAS  PubMed  Google Scholar 

  127. Oudin, M. J. et al. Characterization of the expression of the pro-metastatic MenaINV isoform during breast tumor progression. Clin. Exp. Metastasis 33, 249–261 (2016). This work characterizes the expression of MENA isoforms in primary tumours.

    Article  CAS  PubMed  Google Scholar 

  128. Goswami, S. et al. Identification of invasion specific splice variants of the cytoskeletal protein Mena present in mammary tumor cells during invasion in vivo. Clin. Exp. Metastasis 26, 153–159 (2009).

    Article  CAS  PubMed  Google Scholar 

  129. Di Modugno, F. et al. Splicing program of human MENA produces a previously undescribed isoform associated with invasive, mesenchymal-like breast tumors. Proc. Natl Acad. Sci. USA 109, 19280–19285 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Bria, E. et al. Prognostic impact of alternative splicing-derived hMENA isoforms in resected, node-negative, non-small-cell lung cancer. Oncotarget 5, 11054–11063 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Balsamo, M. et al. The alternatively-included 11a sequence modifies the effects of Mena on actin cytoskeletal organization and cell behavior. Sci. Rep. 6, 35298 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Di Modugno, F. et al. Molecular cloning of hMena (ENAH) and its splice variant hMena+11a: epidermal growth factor increases their expression and stimulates hMena+11a phosphorylation in breast cancer cell lines. Cancer Res. 67, 2657–2665 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Philippar, U. et al. A Mena invasion isoform potentiates EGF-induced carcinoma cell invasion and metastasis. Dev. Cell 15, 813–828 (2008). This work identifies MENA isoforms.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Houck, K. A. et al. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol. Endocrinol. 5, 1806–1814 (1991).

    Article  CAS  PubMed  Google Scholar 

  135. Bates, D. O. et al. VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, is down-regulated in renal cell carcinoma. Cancer Res. 62, 4123–4131 (2002). This work identifies VEGF isoforms.

    CAS  PubMed  Google Scholar 

  136. Woolard, J. et al. VEGF165b, an inhibitory vascular endothelial growth factor splice variant: mechanism of action, in vivo effect on angiogenesis and endogenous protein expression. Cancer Res. 64, 7822–7835 (2004).

    Article  CAS  PubMed  Google Scholar 

  137. Nowak, D. G. et al. Regulation of vascular endothelial growth factor (VEGF) splicing from pro-angiogenic to anti-angiogenic isoforms: a novel therapeutic strategy for angiogenesis. J. Biol. Chem. 285, 5532–5540 (2010).

    Article  CAS  PubMed  Google Scholar 

  138. Harper, S. J. & Bates, D. O. VEGF-A splicing: the key to anti-angiogenic therapeutics? Nat. Rev. Cancer 8, 880–887 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Pritchard-Jones, R. O. et al. Expression of VEGFxxxb, the inhibitory isoforms of VEGF, in malignant melanoma. Br. J. Cancer 97, 223–230 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Varey, A. H. et al. VEGF 165 b, an antiangiogenic VEGF-A isoform, binds and inhibits bevacizumab treatment in experimental colorectal carcinoma: balance of pro- and antiangiogenic VEGF-A isoforms has implications for therapy. Br. J. Cancer 98, 1366–1379 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Biselli-Chicote, P. M. et al. Overexpression of antiangiogenic vascular endothelial growth factor isoform and splicing pegulatory factors in oral, laryngeal and pharyngeal squamous cell carcinomas. Asian Pac. J. Cancer Prev. 18, 2171–2177 (2017).

    PubMed  PubMed Central  Google Scholar 

  142. Rennel, E. et al. The endogenous anti-angiogenic VEGF isoform, VEGF165b inhibits human tumour growth in mice. Br. J. Cancer 98, 1250–1257 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Robertson, C. The extracellular matrix in breast cancer predicts prognosis through composition, splicing, and crosslinking. Exp. Cell Res. 343, 73–81 (2016).

    Article  CAS  PubMed  Google Scholar 

  144. Nam, J. M., Onodera, Y., Bissell, M. J. & Park, C. C. Breast cancer cells in three-dimensional culture display an enhanced radioresponse after coordinate targeting of integrin α5β1 and fibronectin. Cancer Res. 70, 5238–5248 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Schiefner, A., Gebauer, M. & Skerra, A. Extra-domain B in oncofetal fibronectin structurally promotes fibrillar head-to-tail dimerization of extracellular matrix protein. J. Biol. Chem. 287, 17578–17588 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Fukuda, T. et al. Mice lacking the EDB segment of fibronectin develop normally but exhibit reduced cell growth and fibronectin matrix assembly in vitro. Cancer Res. 62, 5603–5610 (2002).

    CAS  PubMed  Google Scholar 

  147. Borsi, L. et al. Expression of different tenascin isoforms in normal, hyperplastic and neoplastic human breast tissues. Int. J. Cancer 52, 688–692 (1992).

    Article  CAS  PubMed  Google Scholar 

  148. Briones-Orta, M. A. et al. Osteopontin splice variants and polymorphisms in cancer progression and prognosis. Biochim. Biophys. Acta 1868, 93–108A (2017).

    CAS  Google Scholar 

  149. Srebrow, A., Blaustein, M. & Kornblihtt, A. R. Regulation of fibronectin alternative splicing by a basement membrane-like extracellular matrix. FEBS Lett. 514, 285–289 (2002).

    Article  CAS  PubMed  Google Scholar 

  150. Bordeleau, F. et al. Tissue stiffness regulates serine/arginine-rich protein-mediated splicing of the extra domain B-fibronectin isoform in tumors. Proc. Natl Acad. Sci. USA 112, 8314–8319 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Martinez, N. M. & Lynch, K. W. Control of alternative splicing in immune responses: many regulators, many predictions, much still to learn. Immunol. Rev. 253, 216–236 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  152. O’Connor, B. P. et al. Regulation of Toll-like receptor signaling by the SF3a mRNA splicing complex. PLoS Genet. 11, 1004932 (2015).

    Article  Google Scholar 

  153. Adib-Conquy, M. et al. Up-regulation of MyD88s and SIGIRR, molecules inhibiting Toll-like receptor signaling, in monocytes from septic patients. Crit. Care Med. 34, 2377–2385 (2006).

    Article  CAS  PubMed  Google Scholar 

  154. De Arras, L. et al. Comparative genomics RNAi screen identifies Eftud2 as a novel regulator of innate immunity. Genetics 197, 485–496 (2014).

    Article  PubMed  Google Scholar 

  155. Poulikakos, P. I. et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480, 387–390 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Wang, Y. et al. The BRCA1- Δ11q alternative splice isoform bypasses germline mutations and promotes therapeutic resistance to PARP inhibition and cisplatin. Cancer Res. 76, 2778–2790 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Ozden, O. et al. Expression of an oncogenic BARD1 splice variant impairs homologous recombination and predicts response to PARP-1 inhibitor therapy in colon cancer. Sci. Rep. 6, 26273 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Ng, K. P. et al. A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nat. Med. 18, 521–528 (2012). This work links resistance to tyrosine kinase inhibitors with BIM splicing.

    Article  CAS  PubMed  Google Scholar 

  159. Castiglioni, F. et al. Role of exon-16-deleted HER2 in breast carcinomas. Endocr. Relat. Cancer 13, 221–232 (2006).

    Article  CAS  PubMed  Google Scholar 

  160. Alajati, A. et al. Mammary tumor formation and metastasis evoked by a HER2 splice variant. Cancer Res. 73, 5320–5327 (2013).

    Article  CAS  PubMed  Google Scholar 

  161. Dehm, S. M., Schmidt, L. J., Heemers, H. V., Vessella, R. L. & Tindall, D. J. Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res. 68, 5469–5477 (2008). This work identifies a constitutively active AR isoform that contributes to therapy resistance.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Antonarakis, E. S. et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N. Engl. J. Med. 371, 1028–1038 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Sun, S. et al. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J. Clin. Invest. 120, 2715–2730 (2010). This work identifies a constitutively active AR isoform that contributes to castration resistance.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Thiebaut, C. et al. The role of ERα36 in development and tumor malignancy. Int. J. Mol. Sci. 21, 4116 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Zheng, S., Asnani, M. & Thomas-Tikhonenko, A. Escape from ALL-CARTaz: leukemia immunoediting in the age of chimeric antigen receptors. Cancer J. 25, 217–222 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Sotillo, E. et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 5, 1282–1295 (2015). This work demonstrates that alternative splicing can enable escape from CAR T cell therapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Zheng, S. et al. Modulation of CD22 protein expression in childhood leukemia by pervasive splicing aberrations: implications for CD22-directed immunotherapies. Blood Cancer Discov. 3, 103–115 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Nakajima, H. et al. New antitumor substances, FR901463, FR901464 and FR901465. II. Activities against experimental tumors in mice and mechanism of action. J. Antibiot. 49, 1204–1211 (1996).

    Article  CAS  Google Scholar 

  169. Thompson, C. F., Jamison, T. F. & Jacobsen, E. N. FR901464: total synthesis, proof of structure, and evaluation of synthetic analogues. J. Am. Chem. Soc. 123, 9974–9983 (2001).

    Article  CAS  PubMed  Google Scholar 

  170. Kaida, D. et al. Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA. Nat. Chem. Biol. 3, 576–583 (2007).

    Article  CAS  PubMed  Google Scholar 

  171. Osman, S. et al. Structural requirements for the antiproliferative activity of pre-mRNA splicing inhibitor FR901464. Chemistry 17, 895–904 (2011).

    Article  CAS  PubMed  Google Scholar 

  172. Albert, B. J., Sivaramakrishnan, A., Naka, T., Czaicki, N. L. & Koide, K. Total syntheses, fragmentation studies, and antitumor/antiproliferative activities of FR901464 and its low picomolar analogue. J. Am. Chem. Soc. 129, 2648–2659 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Liu, X. et al. Genomics-guided discovery of thailanstatins A, B, and C As pre-mRNA splicing inhibitors and antiproliferative agents from Burkholderia thailandensis MSMB43. J. Nat. Prod. 76, 685–693 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Corrionero, A., Minana, B. & Valcarcel, J. Reduced fidelity of branch point recognition and alternative splicing induced by the anti-tumor drug spliceostatin A. Genes. Dev. 25, 445–459 (2011). This work characterizes the mechanism of action of spliceostatin A.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Seiler, M. et al. H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers. Nat. Med. 24, 497–504 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Hong, D. S. et al. A phase I, open-label, single-arm, dose-escalation study of E7107, a precursor messenger ribonucleic acid (pre-mRNA) splicesome inhibitor administered intravenously on days 1 and 8 every 21 days to patients with solid tumors. Invest. N. Drugs 32, 436–444 (2014).

    Article  CAS  Google Scholar 

  177. Eskens, F. A. et al. Phase I pharmacokinetic and pharmacodynamic study of the first-in-class spliceosome inhibitor E7107 in patients with advanced solid tumors. Clin. Cancer Res. 19, 6296–6304 (2013).

    Article  CAS  PubMed  Google Scholar 

  178. Steensma, D. P. et al. Phase I first-in-human dose escalation study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms. Leukemia 35, 3542–3550 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. O’Brien, K., Matlin, A. J., Lowell, A. M. & Moore, M. J. The biflavonoid isoginkgetin is a general inhibitor of pre-mRNA splicing. J. Biol. Chem. 283, 33147–33154 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  180. Vanzyl, E. J. et al. The spliceosome inhibitors isoginkgetin and pladienolide B induce ATF3-dependent cell death. PLoS ONE 15, e0224953 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Yoon, S. O., Shin, S., Lee, H. J., Chun, H. K. & Chung, A. S. Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt-dependent matrix metalloproteinase-9 expression. Mol. Cancer Ther. 5, 2666–2675 (2006).

    Article  CAS  PubMed  Google Scholar 

  182. Darrigrand, R. et al. Isoginkgetin derivative IP2 enhances the adaptive immune response against tumor antigens. Commun. Biol. 4, 269 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Han, T. et al. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science 356, 3755 (2017). This work identifies RBM39 as the molecular target of indisulam.

    Article  Google Scholar 

  184. Ting, T. C. et al. Aryl sulfonamides degrade RBM39 and RBM23 by recruitment to CRL4–DCAF15. Cell Rep. 29, 1499–1510.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Bussiere, D. E. et al. Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex. Nat. Chem. Biol. 16, 15–23 (2020).

    Article  CAS  PubMed  Google Scholar 

  186. Tari, M. et al. U2AF65 assemblies drive sequence-specific splice site recognition. EMBO Rep. 20, 47604 (2019).

    Article  Google Scholar 

  187. Stepanyuk, G. A. et al. UHM–ULM interactions in the RBM39–U2AF65 splicing-factor complex. Acta Crystallogr. D. Struct. Biol. 72, 497–511 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Loerch, S., Maucuer, A., Manceau, V., Green, M. R. & Kielkopf, C. L. Cancer-relevant splicing factor CAPERα engages the essential splicing factor SF3b155 in a specific ternary complex. J. Biol. Chem. 289, 17325–17337 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Kralovicova, J. et al. PUF60-activated exons uncover altered 3′ splice-site selection by germline missense mutations in a single RRM. Nucleic Acids Res. 46, 6166–6187 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Mai, S. et al. Global regulation of alternative RNA splicing by the SR-rich protein RBM39. Biochim. Biophys. Acta 1859, 1014–1024 (2016).

    Article  CAS  PubMed  Google Scholar 

  191. Xu, Y., Nijhuis, A. & Keun, H. C. RNA-binding motif protein 39 (RBM39): an emerging cancer target. Br. J. Pharmacol. 179, 2795–2812 (2020).

    Article  Google Scholar 

  192. Hamid, O. et al. A randomized, open-label clinical trial of tasisulam sodium versus paclitaxel as second-line treatment in patients with metastatic melanoma. Cancer 120, 2016–2024 (2014).

    Article  CAS  PubMed  Google Scholar 

  193. Bezzi, M. et al. Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery. Genes Dev. 27, 1903–1916 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Radzisheuskaya, A. et al. PRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemia. Nat. Struct. Mol. Biol. 26, 999–1012 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Fong, J. Y. et al. Therapeutic targeting of RNA splicing catalysis through inhibition of protein arginine methylation. Cancer Cell 36, 194–209.e9 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Gammons, M. V. et al. Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD. Invest. Ophthalmol. Vis. Sci. 54, 6052–6062 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Hatcher, J. M. et al. SRPKIN-1: a covalent SRPK1/2 inhibitor that potently converts VEGF from pro-angiogenic to anti-angiogenic isoform. Cell Chem. Biol. 25, 460–470.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Batson, J. et al. Development of potent, selective SRPK1 inhibitors as potential topical therapeutics for neovascular eye disease. ACS Chem. Biol. 12, 825–832 (2017).

    Article  CAS  PubMed  Google Scholar 

  199. Sakuma, M., Iida, K. & Hagiwara, M. Deciphering targeting rules of splicing modulator compounds: case of TG003. BMC Mol. Biol. 16, 16 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  200. Babu, N. et al. Phosphoproteomic analysis identifies CLK1 as a novel therapeutic target in gastric cancer. Gastric Cancer 23, 796–810 (2020).

    Article  CAS  PubMed  Google Scholar 

  201. Uzor, S. et al. CDC2-like (CLK) protein kinase inhibition as a novel targeted therapeutic strategy in prostate cancer. Sci. Rep. 11, 7963 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Sohail, M. et al. A novel class of inhibitors that target SRSF10 and promote p53-mediated cytotoxicity on human colorectal cancer cells. Nar. Cancer 3, 19 (2021).

    Article  Google Scholar 

  203. Hluchy, M. et al. CDK11 regulates pre-mRNA splicing by phosphorylation of SF3B1. Nature 609, 829–834 (2022).

    Article  CAS  PubMed  Google Scholar 

  204. Sheridan, C. First small-molecule drug targeting RNA gains momentum. Nat. Biotechnol. 39, 6–8 (2021).

    Article  CAS  PubMed  Google Scholar 

  205. Baranello, G. et al. Risdiplam in type 1 spinal muscular atrophy. N. Engl. J. Med. 384, 915–923 (2021). This work demonstrates that risdiplam increases SMN protein levels in patients with spinal muscular atrophy.

    Article  CAS  PubMed  Google Scholar 

  206. Sivaramakrishnan, M. et al. Binding to SMN2 pre-mRNA–protein complex elicits specificity for small molecule splicing modifiers. Nat. Commun. 8, 1476 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  207. Costales, M. G., Childs-Disney, J. L., Haniff, H. S. & Disney, M. D. How we think about targeting RNA with small molecules. J. Med. Chem. 63, 8880–8900 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Umuhire Juru, A. & Hargrove, A. E. Frameworks for targeting RNA with small molecules. J. Biol. Chem. 296, 100191 (2021).

    Article  CAS  PubMed  Google Scholar 

  209. Havens, M. A. & Hastings, M. L. Splice-switching antisense oligonucleotides as therapeutic drugs. Nucleic Acids Res. 44, 6549–6563 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  210. Bennett, C. F. & Swayze, E. E. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu. Rev. Pharmacol. Toxicol. 50, 259–293 (2010).

    Article  CAS  PubMed  Google Scholar 

  211. Kim, Y. et al. Enhanced potency of GalNAc-conjugated antisense oligonucleotides in hepatocellular cancer models. Mol. Ther. 27, 1547–1557 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Scharner, J., Qi, S., Rigo, F., Bennett, C. F. & Krainer, A. R. Delivery of GalNAc-conjugated splice-switching ASOs to non-hepatic cells through ectopic expression of asialoglycoprotein receptor. Mol. Ther. Nucleic Acids 16, 313–325 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Juliano, R. L. The delivery of therapeutic oligonucleotides. Nucleic Acids Res. 44, 6518–6548 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  214. Li, Z. et al. Pro-apoptotic effects of splice-switching oligonucleotides targeting Bcl-x pre-mRNA in human glioma cell lines. Oncol. Rep. 35, 1013–1019 (2016).

    Article  CAS  PubMed  Google Scholar 

  215. Sun, Y., Yan, L., Guo, J., Shao, J. & Jia, R. Downregulation of SRSF3 by antisense oligonucleotides sensitizes oral squamous cell carcinoma and breast cancer cells to paclitaxel treatment. Cancer Chemother. Pharmacol. 84, 1133–1143 (2019).

    Article  CAS  PubMed  Google Scholar 

  216. Leclair, N. K. et al. Poison exon splicing regulates a coordinated network of SR protein expression during differentiation and tumorigenesis. Mol. Cell 80, 648–665.e9 (2020). This work identifies functional roles for poison exons in tumorigenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Denichenko, P. et al. Specific inhibition of splicing factor activity by decoy RNA oligonucleotides. Nat. Commun. 10, 1590 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  218. Gadgil, A. & Raczynska, K. D. U7 snRNA: a tool for gene therapy. J. Gene Med. 23, 3321 (2021).

    Article  Google Scholar 

  219. Rogalska, M. E. et al. Therapeutic activity of modified U1 core spliceosomal particles. Nat. Commun. 7, 11168 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Wang, Y., Cheong, C. G., Hall, T. M. & Wang, Z. Engineering splicing factors with designed specificities. Nat. Methods 6, 825–830 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Cox, D. B. T. et al. RNA editing with CRISPR–Cas13. Science 358, 1019–1027 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Konermann, S. et al. Transcriptome engineering with RNA-targeting type VI-D CRISPR effectors. Cell 173, 665–676.e14 (2018). This work uses RNA-targeting Cas to manipulate alternative splicing.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Du, M., Jillette, N., Zhu, J. J., Li, S. & Cheng, A. W. CRISPR artificial splicing factors. Nat. Commun. 11, 2973 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Gapinske, M. et al. CRISPR–SKIP: programmable gene splicing with single base editors. Genome Biol. 19, 107 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  225. Banas, K. et al. Exon skipping induced by CRISPR-directed gene editing regulates the response to chemotherapy in non-small cell lung carcinoma cells. Gene Ther. 29, 357–367 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Thomas, J. D. et al. RNA isoform screens uncover the essentiality and tumor-suppressor activity of ultraconserved poison exons. Nat. Genet. 52, 84–94 (2020). This work reveals tumour-suppressive roles for poison exons.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Smith, C. C. et al. Alternative tumour-specific antigens. Nat. Rev. Cancer 19, 465–478 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Vauchy, C. et al. CD20 alternative splicing isoform generates immunogenic CD4 helper T epitopes. Int. J. Cancer 137, 116–126 (2015).

    Article  CAS  PubMed  Google Scholar 

  229. Oka, M. et al. Aberrant splicing isoforms detected by full-length transcriptome sequencing as transcripts of potential neoantigens in non-small cell lung cancer. Genome Biol. 22, 9 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  231. Frankiw, L., Baltimore, D. & Li, G. Alternative mRNA splicing in cancer immunotherapy. Nat. Rev. Immunol. 19, 675–687 (2019).

    Article  CAS  PubMed  Google Scholar 

  232. Slansky, J. E. & Spellman, P. T. Alternative splicing in tumors—a path to immunogenicity? N. Engl. J. Med. 380, 877–880 (2019).

    Article  PubMed  Google Scholar 

  233. Hoyos, L. E. & Abdel-Wahab, O. Cancer-specific splicing changes and the potential for splicing-derived neoantigens. Cancer Cell 34, 181–183 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Bowling, E. A. et al. Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer. Cell 184, 384–403.e21 (2021). This work shows that inhibition of the SF3b complex triggers antiviral signalling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Lu, S. X. et al. Pharmacologic modulation of RNA splicing enhances anti-tumor immunity. Cell 184, 4032–4047.e31 (2021). This work demonstrates that splicing modulation triggers neoantigen production and synergizes with immune checkpoint blockade.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. De Paoli-Iseppi, R., Gleeson, J. & Clark, M. B. Isoform age—splice isoform profiling using long-read technologies. Front. Mol. Biosci. 8, 711733 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  237. Veiga, D. F. T. et al. A comprehensive long-read isoform analysis platform and sequencing resource for breast cancer. Sci. Adv. 8, eabg6711 (2022). This work identifies full-length isoforms in primary tumours using LR-seq.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Tian, L. et al. Comprehensive characterization of single-cell full-length isoforms in human and mouse with long-read sequencing. Genome Biol. 22, 310 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Gupta, I. et al. Single-cell isoform RNA sequencing characterizes isoforms in thousands of cerebellar cells. Nat. Biotechnol. 36, 1197–1202 (2018).

    Article  CAS  Google Scholar 

  240. Hardwick, S. A. et al. Single-nuclei isoform RNA sequencing unlocks barcoded exon connectivity in frozen brain tissue. Nat. Biotechnol. 40, 1082–1092 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Joglekar, A. et al. A spatially resolved brain region- and cell type-specific isoform atlas of the postnatal mouse brain. Nat. Commun. 12, 463 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Mou, H. et al. CRISPR/Cas9-mediated genome editing induces exon skipping by alternative splicing or exon deletion. Genome Biol. 18, 108 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  243. Urbanski, L. et al. MYC regulates a pan-cancer network of co-expressed oncogenic splicing factors. Cell Rep. 41, 11704 (2022).

    Article  Google Scholar 

  244. Hsu, T. Y. et al. The spliceosome is a therapeutic vulnerability in MYC-driven cancer. Nature 525, 384–388 (2015). This work identifies a MYC-driven splicing vulnerability.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Rossbach, O. et al. Auto- and cross-regulation of the hnRNP L proteins by alternative splicing. Mol. Cell Biol. 29, 1442–1451 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Lareau, L. F., Inada, M., Green, R. E., Wengrod, J. C. & Brenner, S. E. Unproductive splicing of SR genes associated with highly conserved and ultraconserved DNA elements. Nature 446, 926–929 (2007). This landmark study identifies conserved poison exons in genes encoding SR proteins.

    Article  CAS  PubMed  Google Scholar 

  247. Ciesla, M. et al. Oncogenic translation directs spliceosome dynamics revealing an integral role for SF3A3 in breast cancer. Mol. Cell 81, 1453–1468.e12 (2021).

    Article  CAS  PubMed  Google Scholar 

  248. Kralovicova, J., Moreno, P. M., Cross, N. C., Pego, A. P. & Vorechovsky, I. Antisense oligonucleotides modulating activation of a nonsense-mediated RNA decay switch exon in the ATM gene. Nucleic Acid. Ther. 26, 392–400 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Mercatante, D. R., Bortner, C. D., Cidlowski, J. A. & Kole, R. Modification of alternative splicing of Bcl-x pre-mRNA in prostate and breast cancer cells. analysis of apoptosis and cell death. J. Biol. Chem. 276, 16411–16417 (2001).

    Article  CAS  PubMed  Google Scholar 

  250. Taylor, J. K., Zhang, Q. Q., Wyatt, J. R. & Dean, N. M. Induction of endogenous Bcl-xS through the control of Bcl-x pre-mRNA splicing by antisense oligonucleotides. Nat. Biotechnol. 17, 1097–1100 (1999).

    Article  CAS  PubMed  Google Scholar 

  251. Liu, J. et al. Overcoming imatinib resistance conferred by the BIM deletion polymorphism in chronic myeloid leukemia with splice-switching antisense oligonucleotides. Oncotarget 8, 77567–77585 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  252. Anczuków, O. et al. BRCA2 deep intronic mutation causing activation of a cryptic exon: opening toward a new preventive therapeutic strategy. Clin. Cancer Res. 18, 4903–4909 (2012).

    Article  PubMed  Google Scholar 

  253. Nielsen, T. O., Sorensen, S., Dagnaes-Hansen, F., Kjems, J. & Sorensen, B. S. Directing HER4 mRNA expression towards the CYT2 isoform by antisense oligonucleotide decreases growth of breast cancer cells in vitro and in vivo. Br. J. Cancer 108, 2291–2298 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Li, L. et al. Targeting the ERG oncogene with splice-switching oligonucleotides as a novel therapeutic strategy in prostate cancer. Br. J. Cancer 123, 1024–1032 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Bruno, I. G., Jin, W. & Cote, G. J. Correction of aberrant FGFR1 alternative RNA splicing through targeting of intronic regulatory elements. Hum. Mol. Genet. 13, 2409–2420 (2004).

    Article  CAS  PubMed  Google Scholar 

  256. Lin, J. et al. Induced-decay of glycine decarboxylase transcripts as an anticancer therapeutic strategy for non-small-cell lung carcinoma. Mol. Ther. Nucleic Acids 9, 263–273 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Karras, J. G., McKay, R. A., Lu, T., Dean, N. M. & Monia, B. P. Antisense inhibition of membrane-bound human interleukin-5 receptor-α chain does not affect soluble receptor expression and induces apoptosis in TF-1 cells. Antisense Nucleic Acid. Drug Dev. 10, 347–357 (2000).

    Article  CAS  PubMed  Google Scholar 

  258. Shieh, J. J., Liu, K. T., Huang, S. W., Chen, Y. J. & Hsieh, T. Y. Modification of alternative splicing of Mcl-1 pre-mRNA using antisense morpholino oligonucleotides induces apoptosis in basal cell carcinoma cells. J. Invest. Dermatol. 129, 2497–2506 (2009).

    Article  CAS  PubMed  Google Scholar 

  259. Shiraishi, T., Eysturskarth, J. & Nielsen, P. E. Modulation of mdm2 pre-mRNA splicing by 9-aminoacridine-PNA (peptide nucleic acid) conjugates targeting intron–exon junctions. BMC Cancer 10, 342 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Dewaele, M. et al. Antisense oligonucleotide-mediated MDM4 exon 6 skipping impairs tumor growth. J. Clin. Invest. 126, 68–84 (2016).

    Article  PubMed  Google Scholar 

  261. Ghigna, C. et al. Pro-metastatic splicing of Ron proto-oncogene mRNA can be reversed: therapeutic potential of bifunctional oligonucleotides and indole derivatives. RNA Biol. 7, 495–503 (2010).

    Article  CAS  PubMed  Google Scholar 

  262. Zammarchi, F. et al. Antitumorigenic potential of STAT3 alternative splicing modulation. Proc. Natl Acad. Sci. USA 108, 17779–17784 (2011). This work demonstrates that ASOs can be used to manipulate splicing in in vivo cancer models.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Izaguirre, D. I. et al. PTBP1-dependent regulation of USP5 alternative RNA splicing plays a role in glioblastoma tumorigenesis. Mol. Carcinog. 51, 895–906 (2012).

    Article  CAS  PubMed  Google Scholar 

  264. Shen, H., Zheng, X., Luecke, S. & Green, M. R. The U2AF35-related protein Urp contacts the 3′ splice site to promote U12-type intron splicing and the second step of U2-type intron splicing. Genes Dev. 24, 2389–2394 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Dvinge, H. & Bradley, R. K. Widespread intron retention diversifies most cancer transcriptomes. Genome Med. 7, 45 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  266. Mehmood, A. et al. Systematic evaluation of differential splicing tools for RNA-seq studies. Brief. Bioinform 21, 2052–2065 (2020).

    Article  CAS  PubMed  Google Scholar 

  267. Shen, S. et al. rMATS: robust and flexible detection of differential alternative splicing from replicate RNA-seq data. Proc. Natl Acad. Sci. USA 111, 5593–5601 (2014).

    Article  Google Scholar 

  268. Katz, Y., Wang, E. T., Airoldi, E. M. & Burge, C. B. Analysis and design of RNA sequencing experiments for identifying isoform regulation. Nat. Methods 7, 1009–1015 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Vaquero-Garcia, J. et al. A new view of transcriptome complexity and regulation through the lens of local splicing variations. eLife 5, 11752 (2016).

    Article  Google Scholar 

  270. Trincado, J. L. et al. SUPPA2: fast, accurate, and uncertainty-aware differential splicing analysis across multiple conditions. Genome Biol. 19, 40 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  271. Li, Y. I. et al. Annotation-free quantification of RNA splicing using LeafCutter. Nat. Genet. 50, 151–158 (2018).

    Article  CAS  PubMed  Google Scholar 

  272. Leger, A. et al. RNA modifications detection by comparative Nanopore direct RNA sequencing. Nat. Commun. 12, 7198 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. He, S. et al. High-plex imaging of RNA and proteins at subcellular resolution in fixed tissue by spatial molecular imaging. Nat. Biotechnol. https://doi.org/10.1038/s41587-022-01483-z (2022).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank members of the Bradley and Anczukow laboratories for helpful discussions. O.A. was supported by the National Institutes of Health (NIH)/National Cancer Institute (NCI) (R01 CA248317 and P30 CA034196) and NIH/National Institute of General Medical Sciences (NIGMS) (R01 GM138541). R.K.B. was supported, in part, by the NIH/NCI (R01 CA251138), NIH/National Heart, Lung, and Blood Institute (NHLBI) (R01 HL128239 and R01 HL151651) and the Blood Cancer Discoveries Grant programme through the Leukaemia & Lymphoma Society, Mark Foundation for Cancer Research and Paul G. Allen Frontiers Group (8023-20). R.K.B. is a Scholar of The Leukaemia & Lymphoma Society (1344-18) and holds the McIlwain Family Endowed Chair in Data Science.

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Correspondence to Robert K. Bradley or Olga Anczuków.

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R.K.B. is an inventor on patent applications filed by Fred Hutchinson Cancer Center related to modulating splicing for cancer therapy. O.A. is an inventor on a patent application filed by The Jackson Laboratory related to modulating splicing factors.

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Nature Reviews Cancer thanks Maria Carmo-Fonseca, Polly Leilei Chen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Branch point

A nucleotide that performs a nucleophilic attack on the 5′ splice site (5′SS) in the first step of splicing.

K homology (KH) domain

A protein domain that can bind RNA and is found in various RNA-binding proteins (RBPs), including splicing factors.

Polypyrimidine tract

A pyrimidine (C or T)-rich sequence motif upstream of many 3′ splice sites (3′SSs) that is bound by the U2AF2 subunit of the U2AF heterodimer to facilitate 3′SS recognition.

RNA splicing

A post-transcriptional mechanism that mediates the removal of introns from a pre-mRNA transcript and the ligation of exons to form a mature mRNA.

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Bradley, R.K., Anczuków, O. RNA splicing dysregulation and the hallmarks of cancer. Nat Rev Cancer 23, 135–155 (2023). https://doi.org/10.1038/s41568-022-00541-7

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