Emerging roles of the spliceosomal machinery in myelodysplastic syndromes and other hematological disorders

Abstract

In humans, the majority of all protein-coding transcripts contain introns that are removed by mRNA splicing carried out by spliceosomes. Mutations in the spliceosome machinery have recently been identified using whole-exome/genome technologies in myelodysplastic syndromes (MDS) and in other hematological disorders. Alterations in splicing factor 3 subunit b1 (SF3b1) were the first spliceosomal mutations described, immediately followed by identification of other splicing factor mutations, including U2 small nuclear RNA auxillary factor 1 (U2AF1) and serine arginine-rich splicing factor 2 (SRSF2). SF3b1/U2AF1/SRSF2 mutations occur at varying frequencies in different disease subtypes, each contributing to differences in survival outcomes. However, the exact functional consequences of these spliceosomal mutations in the pathogenesis of MDS and other hematological malignancies remain largely unknown and subject to intense investigation. For SF3b1, a gain of function mutation may offer the promise of new targeted therapies for diseases that carry this molecular abnormality that can potentially lead to cure. This review aims to provide a comprehensive overview of the emerging role of the spliceosome machinery in the biology of MDS/hematological disorders with an emphasis on the functional consequences of mutations, their clinical significance, and perspectives on how they may influence our understanding and management of diseases affected by these mutations.

Figure 1. Alternative splicing pattern and disease causation

Left panel: Spliceosomes catalyze RNA splicing which leads to the ligation of two flanking exonic regions. The GU dinucleotide at the 5′ end, BPS and terminal AG dinucleotide at the 3′ end serve as specific recognition sites. Three different complexes (E, A, and B) are subsequently formed by the spliceosome assembly. In order, U1, U2, U4/U5/U6snRNP all cooperate in the formation of each complex. SF3b1 encodes a protein responsible for the binding of the U2snRNP to the branch point at the 3′ splicing site. Right panel: alternative splicing is the process which generates variability in transcripts, ultimately leading to biological differences in protein function and structure through different mechanisms (A–G). The first type is called A) exon skipping or sometimes called exon cassette which involves either retention or splicing out of the involved exon from the primary transcript. It is the most common mode of alternative splicing in mammalian pre-mRNA. In B) mutually exclusive exons, one of two exons are retained in the primary transcript after splicing. In C) competitive 5′ splice site, a new 5′ splice junction is used. In D) competive 3′ splice site, a new 3′ splice junction is used. In E) retained intron, a sequence is spliced out or kept. In F) multiple promoters, a transcriptional process where different starting points in the transcription can lead to transcripts with different 5′ sites. In G) multiple Poly-A sites, is the process that generates different 3′ ends. Several hypotheses are illustrated to explain the disease causation. (Illustrated by Ramon V. Tiu, MD)