RNA splicing
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.
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.
In one picture
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.
Diagram
top- 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)
Notes
top- Leading programmes: Abdel-Wahab (MSK) on spliceosome mutations; Bradley (Fred Hutch) on splicing and neoantigens; Ebert (Dana-Farber) on SF3B1 in MDS.