title: Distinct splicing signatures affect converged pathways in myelodysplastic syndrome patients carrying mutations in different splicing regulators.
abstract: 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.
authors: Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors: Jinsong
authors: J
authors: Qiu
authors: Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors: Bing
authors: B
authors: Zhou
authors: Department of Hematology, Hemostasis, Oncology and Stem cell Transplantation, Hannover Medical School, 30625 Hannover, Germany.
authors: Felicitas
authors: F
authors: Thol
authors: Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors: Yu
authors: Y
authors: Zhou
authors: Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors: Liang
authors: L
authors: Chen
authors: Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors: Changwei
authors: C
authors: Shao
authors: Institute for Genomic Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors: Christopher
authors: C
authors: DeBoever
authors: Clinical and Translational Research Institute, University of California, San Diego, La Jolla, California 92093, USA.
authors: Jiayi
authors: J
authors: Hou
authors: Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors: Hairi
authors: H
authors: Li
authors: Department of Hematology, Hemostasis, Oncology and Stem cell Transplantation, Hannover Medical School, 30625 Hannover, Germany.
authors: Anuhar
authors: A
authors: Chaturvedi
authors: Department of Hematology, Hemostasis, Oncology and Stem cell Transplantation, Hannover Medical School, 30625 Hannover, Germany.
authors: Arnold
authors: A
authors: Ganser
authors: Division of Hematology-Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors: Rafael
authors: R
authors: Bejar
authors: Department of Pathology, Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors: Dong-Er
authors: DE
authors: Zhang
authors: Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA Institute for Genomic Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors: Xiang-Dong
authors: XD
authors: Fu
authors: Department of Hematology, Hemostasis, Oncology and Stem cell Transplantation, Hannover Medical School, 30625 Hannover, Germany.
authors: Michael
authors: M
authors: Heuser
mesh_terms: 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 / Q000235:genetics* / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics*; D022821:RNA Splice Sites; D012326:RNA Splicing; D000072260:RNA Splicing Factors / Q000235:genetics*; D000068103:Serine-Arginine Splicing Factors / Q000235:genetics*; D000072668:Splicing Factor U2AF / Q000235:genetics*
chemical_list: D010750:Phosphoproteins; D022821:RNA Splice Sites; D000072260:RNA Splicing Factors; C112491:SF3B1 protein, human; D000072668:Splicing Factor U2AF; C076753:U2AF1 protein, human; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors
keywords: RASL-seq; diagnostic and prognostic splicing signatures; myelodysplastic syndromes (MDS); pre-mRNA splicing; splicing factor mutations