{"entity":{"id":"rna-splicing","kind":"pathway","name":"RNA splicing","aka":[],"tldr":"Genes are cut and pasted into messages before they are used. Blood cancers often carry mutations in the splicing machinery, and the errors create abnormal proteins that could serve as targets or immune flags.","summary":"Spliceosome mutations (SF3B1, SRSF2, U2AF1, ZRSR2) occur in ~50% of MDS and in CLL and uveal melanoma; they cause mis-splicing, R-loops, and dependence on the remaining wild-type spliceosome (H3B-8800, negative), and on PRMT5 and NMD. Splicing produces drug-resistance isoforms (AR-V7 in prostate cancer, BCL2L1 isoforms) and neoantigens (splice-junction-derived) that may be immunogenic across patients. RNA-targeting small molecules (risdiplam-like) and antisense oligonucleotides are the therapeutic tools; MYC-driven tumours are spliceosome-dependent.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/RNA_splicing","links":[{"label":"Bradley & Anczuków, RNA splicing dysregulation and the hallmarks of cancer (Nature Reviews Cancer 2023)","url":"https://doi.org/10.1038/s41568-022-00541-7"}],"tags":["mechanism"],"related":[],"cancers":["aml","cll","melanoma","prostate"],"sections":[],"technologies":["antisense-sirna","rna-seq"],"targets":["androgen-receptor"],"drugs":[],"companies":[],"institutions":["mskcc","dana-farber","fred-hutch"],"pathways":["myc","replication-stress","ar-signaling","antigen-presentation-immunoediting"],"terms":["ar-v7","neoantigen"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-bradley-nat-rev-cancer"],"journals":[],"dependsOn":[],"notes":["Leading programmes: Abdel-Wahab (MSK) on spliceosome mutations; Bradley (Fred Hutch) on splicing and neoantigens; Ebert (Dana-Farber) on SF3B1 in MDS."],"analogy":"Splicing is film editing. The raw footage (pre-mRNA) is cut into a final movie. Cancer's editor makes odd cuts: some create villains (AR-V7), some create scenes no one has seen before (neoantigens), and the editing room itself becomes a place where the cancer can be attacked.","nodes":[{"id":"pre","label":"Pre-mRNA","x":12,"y":40},{"id":"sf3b1","label":"SF3B1 / SRSF2 / U2AF1 (mutant)","x":38,"y":20},{"id":"spl","label":"Spliceosome","x":38,"y":60},{"id":"iso","label":"Aberrant isoforms (AR-V7)","x":66,"y":25,"targetId":"androgen-receptor"},{"id":"neo","label":"Splice neoantigens","x":66,"y":60},{"id":"rloop","label":"R-loops, replication stress","x":66,"y":90},{"id":"prmt5","label":"PRMT5 dependence","x":90,"y":60}],"edges":[{"from":"pre","to":"spl","type":"activates"},{"from":"sf3b1","to":"spl","type":"activates"},{"from":"spl","to":"iso","type":"activates"},{"from":"spl","to":"neo","type":"activates"},{"from":"sf3b1","to":"rloop","type":"activates"},{"from":"spl","to":"prmt5","type":"activates"}],"interventions":["Spliceosome modulators (H3B-8800 negative; next generation in development)","PRMT5 inhibitors in MTAP-deleted and splicing-mutant cancers","Antisense oligonucleotides to redirect splicing (AR-V7, BCL2L1)","Splice-derived neoantigen vaccines (research)"]},"route":"/pathways/rna-splicing/","neighbours":{"cancer":[{"id":"aml","kind":"cancer","name":"Acute myeloid leukaemia","route":"/cancers/aml/"},{"id":"cll","kind":"cancer","name":"Chronic lymphocytic leukaemia","route":"/cancers/cll/"},{"id":"cmml","kind":"cancer","name":"Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms","route":"/cancers/cmml/"},{"id":"melanoma","kind":"cancer","name":"Melanoma","route":"/cancers/melanoma/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"technology":[{"id":"antisense-sirna","kind":"technology","name":"Oligonucleotide therapeutics","route":"/technologies/antisense-sirna/"},{"id":"rna-seq","kind":"technology","name":"RNA sequencing & expression profiling","route":"/technologies/rna-seq/"}],"target":[{"id":"androgen-receptor","kind":"target","name":"Androgen receptor","route":"/targets/androgen-receptor/"},{"id":"sf3b1","kind":"target","name":"SF3B1","route":"/targets/sf3b1/"},{"id":"srsf2","kind":"target","name":"SRSF2","route":"/targets/srsf2/"},{"id":"u2af1","kind":"target","name":"U2AF1","route":"/targets/u2af1/"}],"institution":[{"id":"dana-farber","kind":"institution","name":"Dana-Farber Brigham Cancer Center","route":"/institutions/dana-farber/"},{"id":"fred-hutch","kind":"institution","name":"Fred Hutchinson Cancer Center","route":"/institutions/fred-hutch/"},{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"}],"pathway":[{"id":"ar-signaling","kind":"pathway","name":"Androgen receptor signalling","route":"/pathways/ar-signaling/"},{"id":"antigen-presentation-immunoediting","kind":"pathway","name":"Antigen presentation & immune editing","route":"/pathways/antigen-presentation-immunoediting/"},{"id":"replication-stress","kind":"pathway","name":"DNA replication stress","route":"/pathways/replication-stress/"},{"id":"myc","kind":"pathway","name":"MYC","route":"/pathways/myc/"}],"term":[{"id":"ar-v7","kind":"term","name":"AR-V7 splice variant","route":"/terms/ar-v7/"},{"id":"neoantigen","kind":"term","name":"Neoantigen","route":"/terms/neoantigen/"}],"paper":[{"id":"paper-antonarakis-ar-v7-resistance-nejm-2014","kind":"paper","name":"AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer","route":"/key-papers/paper-antonarakis-ar-v7-resistance-nejm-2014/"},{"id":"paper-scher-nuclear-arv7-taxane-vs-arsi-jama-oncol-2018","kind":"paper","name":"Nuclear-localised androgen receptor splice variant 7 in circulating tumour cells as a predictive biomarker in castration-resistant prostate cancer","route":"/key-papers/paper-scher-nuclear-arv7-taxane-vs-arsi-jama-oncol-2018/"},{"id":"paper-prophecy-arv7-validation-jco-2019","kind":"paper","name":"PROPHECY: prospective multicentre validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer","route":"/key-papers/paper-prophecy-arv7-validation-jco-2019/"},{"id":"paper-bradley-nat-rev-cancer","kind":"paper","name":"RNA splicing dysregulation and the hallmarks of cancer","route":"/key-papers/paper-bradley-nat-rev-cancer/"},{"id":"paper-armenia-long-tail-oncogenic-drivers-prostate-nat-genet-2018","kind":"paper","name":"The long tail of oncogenic drivers in prostate cancer","route":"/key-papers/paper-armenia-long-tail-oncogenic-drivers-prostate-nat-genet-2018/"}],"idea":[{"id":"idea-splice-neoantigens","kind":"idea","name":"Shared splice-derived neoantigens as off-the-shelf vaccine targets","route":"/ideas/idea-splice-neoantigens/"}]}}