How do messenger RNA splicing alterations drive myelodysplasia?

Abstract

Mutations in RNA splicing factors are the single most common class of genetic alterations in myelodysplastic syndrome (MDS) patients. Although much has been learned about how these mutations affect splicing at a global-and transcript-specific level, critical questions about the role of these mutations in MDS development and maintenance remain. Here we present the questions to be addressed in order to understand the unique enrichment of these mutations in MDS. (Blood. 2017; 129(18):2465-2470 IntroductionMyelodysplastic syndromes (MDSs) represent clonal disorders of hematopoietic stem cells (HSCs) whereby hematopoietic cell-intrinsic genetic alterations as well as non-cell autonomous factors contribute to an aberrant HSC that produces morphologically abnormal progeny and has impaired ability to generate mature blood cells. Due to the wide clinical and morphologic heterogeneity of MDS, substantial effort has been placed on characterizing the genetic alterations present in MDS cells in hopes of improving our ability to understand, diagnose, and treat the disease. Extensive targeted mutational analysis of protein coding genes has identified that MDS is characterized by a high frequency of mutations in genes encoding messenger RNA (mRNA) splicing factors as well as epigenetic modifiers.1-3 The discovery of mutations in RNA splicing factors in particular was quite unexpected as these mutations are generally uncommon in cancer yet are present in 50% to 60% of MDS patients. Interestingly, there are clear associations between specific mutated splicing factors and subtypes of MDS, most notably mutations in the RNA splicing factor SF3B1 in .90% of patients with MDS with ring sideroblasts.1,2,4 Moreover, the nature of these mutations is quite conspicuous as they occur as heterozygous point mutations at highly recurrent residues. Finally, within MDS patients, these mutations are almost always mutually exclusive; an MDS patient almost never has .1 RNA splicing factor mutation at the same time [1][2][3] (although rare individuals with mutations in .1 RNA splicing factor have been noted, 5 these occur far less frequently than expected by chance in MDS and it is unclear if both mutations in such cases are present within the same cell and/or how the mutations may impact splicing if coexpressed in the same cell).The discovery of RNA splicing factor mutations has led to intense efforts to understand their biological impact on hematopoiesis, 6-9 their genomic and biochemical effects on RNA splicing, 10-21 their structural effects, 22 and potential means to therapeutically target cells bearing these mutations. 8,[23][24][25] Although there have been major advances in understanding the role of RNA splicing factor mutations in MDS pathogenesis and therapy (as reviewed recently [26][27][28] ), major questions about their biological consequences within cells, requirement in disease initiation vs maintenance, and cell autonomous vs nonautonomous roles remain. In addition, numerous questions about the structural and biochemical effects of...

Clinical features and biological implications of different U2AF1 mutation types in myelodysplastic syndromes

“…Besides SF3B1 , U2AF1 is a common (∼10%) mutated spliceosome gene in MDS . Understanding the clinical features and biological implications of U2AF1 mutation ( U2AF1 MT) in MDS is only just beginning to emerge …”

“…5,6,10,[16][17][18] Understanding the clinical features and biological implications of U2AF1 mutation (U2AF1MT) in MDS is only just beginning to emerge. [19][20][21] To investigate the clinical impact of U2AF1MT in MDS, we studied a cohort of 511 patients. We compared the mutational landscapes of U2AF1MT subjects, their clinical associations, survival, and clonal hierarchies.…”

The yeast core spliceosome maintains genome integrity through R-loop prevention and α-tubulin expression

“…Defects in RNA processing have been implicated in genome instability across species, and in both human cancer and repeat-expansion diseases (Richard and Manley, 2017). Indeed, RNA splicing factors are frequently lost or mutated in various cancers where they shift gene expression landscapes, favoring oncogenesis (Darman et al, 2015; Dolatshad et al, 2015; Joshi et al, 2017). The detailed role of splicing in preventing genome instability is still unclear.…”

Characterization by Next Generation Sequencing of mutations of spliceosome genes and bone marrow mesenchymal cells in patients with myelodysplastic syndromes

“…Splicing process represents the key link between transcription and translation, that allows the production of multiple mRNA isoforms of more than 90% of human protein-coding genes [62]. This process consists in removing introns and joining exons together in order to produce a mature mRNA molecule [63].…”

“…Among the different hotspot codons (622, 625, 662, 666 and 700), missense substitutions at codon 700 (p.K700E), are the most frequent point mutation [72,73]. All these mutations led to a gain of function [62].Hotspot mutations in this gene result in an out-offrame splicing event for a subset of transcripts [62,70,74].…”