Distinct splicing signatures affect converged pathways in myelodysplastic syndrome patients carrying mutations in different splicing regulators.
Myelodysplastic syndromes (MDS) are heterogeneous myeloid disorders with prevalent mutations in several splicing factors, but the splicing programs linked to specific mutations or MDS in general remain to be systematically defined. We applied RASL-seq, a sensitive and cost-effective platform, to interrogate 5502 annotated splicing events in 169 samples from MDS patients or healthy individuals. We found that splicing signatures associated with normal hematopoietic lineages are largely related to cell signaling and differentiation programs, whereas MDS-linked signatures are primarily involved in cell cycle control and DNA damage responses. Despite the shared roles of affected splicing factors in the 3' splice site definition, mutations in U2AF1, SRSF2, and SF3B1 affect divergent splicing programs, and interestingly, the affected genes fall into converging cancer-related pathways. A risk score derived from 11 splicing events appears to be independently associated with an MDS prognosis and AML transformation, suggesting potential clinical relevance of altered splicing patterns in MDS.
['Qiu|Jinsong|J|', 'Zhou|Bing|B|', 'Thol|Felicitas|F|', 'Zhou|Yu|Y|', 'Chen|Liang|L|', 'Shao|Changwei|C|', 'DeBoever|Christopher|C|', 'Hou|Jiayi|J|', 'Li|Hairi|H|', 'Chaturvedi|Anuhar|A|', 'Ganser|Arnold|A|', 'Bejar|Rafael|R|', 'Zhang|Dong-Er|DE|', 'Fu|Xiang-Dong|XD|', 'Heuser|Michael|M|']
D000328:Adult D000368:Aged D000369:Aged, 80 and over D016022:Case-Control Studies D005260:Female D006801:Humans D008297:Male D008875:Middle Aged D009154:Mutation D009190:Myelodysplastic Syndromes D010750:Phosphoproteins D022821:RNA Splice Sites D012326:RNA Splicing D000072260:RNA Splicing Factors D000068103:Serine-Arginine Splicing Factors D000072668:Splicing Factor U2AF
myelodysplastic syndromes (MDS) RASL-seq diagnostic and prognostic splicing signatures pre-mRNA splicing splicing factor mutations