Complex landscape of alternative splicing in myeloid neoplasms

Area of Science:

• Molecular Biology
• Genetics
• Oncology

Background:

• Myeloid neoplasms frequently harbor mutations in spliceosome components, affecting pre-messenger RNA (pre-mRNA) splicing.
• Specific mutations in splicing factors (SF) like SF3B1, SRSF2, U2AF1, and ZRSR2 lead to distinct aberrant splicing signatures.
• Previous research lacked the statistical power to identify commonly mis-spliced transcripts across diverse patient groups.

Purpose of the Study:

• To identify transcripts frequently mis-spliced by mutated splicing factors in myeloid neoplasms.
• To discover rare splicing factor mutations associated with common alternative splicing (AS) signatures.
• To characterize SF-dependent neojunctions and understand the functional impact of mis-splicing on protein function.

Main Methods:

• RNA sequencing (RNA-Seq) was performed on bone marrow samples from 1258 myeloid neoplasm patients and 63 healthy donors.
• A computational pipeline was used to analyze 17,300 dysregulated AS events and predict their impact on protein function.
• Meta-splicing analysis was conducted to compare splicing patterns between disease and healthy samples.

Main Results:

• Identified transcripts commonly mis-spliced by mutated splicing factors (SF).
• Discovered rare SF mutations exhibiting common alternative splicing (AS) signatures.
• Observed reduced levels of retained introns in myeloid neoplasms, particularly in patients with SF mutations.
• Characterized 17,300 targets of SF mutation-induced mis-splicing, revealing a pathway promoting proliferation.

Conclusions:

• Aberrant alternative splicing (AS) driven by splicing factor mutations is a hallmark of myeloid neoplasms.
• A common mechanism involving reduced retained introns, similar to 'detained introns,' may contribute to maintaining a proliferative state in cancer cells.
• This study provides functional characterization of numerous mis-splicing targets, elucidating a pathway linking AS to cancer cell proliferation.