Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis.
Myelodysplastic syndromes (MDSs) are chronic and often progressive myeloid neoplasms associated with remarkable heterogeneity in the histomorphology and clinical course. Various somatic mutations are involved in the pathogenesis of MDS. Recently, mutations in a gene encoding a spliceosomal protein, SF3B1, were discovered in a distinct form of MDS with ring sideroblasts. Whole exome sequencing of 15 patients with myeloid neoplasms was performed, and somatic mutations in spliceosomal genes were identified. Sanger sequencing of 310 patients was performed to assess phenotype/genotype associations. To determine the functional effect of spliceosomal mutations, we evaluated pre-mRNA splicing profiles by RNA deep sequencing. We identified additional somatic mutations in spliceosomal genes, including SF3B1, U2AF1, and SRSF2. These mutations alter pre-mRNA splicing patterns. SF3B1 mutations are prevalent in low-risk MDS with ring sideroblasts, whereas U2AF1 and SRSF2 mutations are frequent in chronic myelomonocytic leukemia and advanced forms of MDS. SF3B1 mutations are associated with a favorable prognosis, whereas U2AF1 and SRSF2 mutations are predictive for shorter survival. Mutations affecting spliceosomal genes that result in defective splicing are a new leukemogenic pathway. Spliceosomal genes are probably tumor suppressors, and their mutations may constitute diagnostic biomarkers that could potentially serve as therapeutic targets.
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
Hideki
H
Makishima
Valeria
V
Visconte
Hirotoshi
H
Sakaguchi
Anna M
AM
Jankowska
Sarah
S
Abu Kar
Andres
A
Jerez
Bartlomiej
B
Przychodzen
Manoj
M
Bupathi
Kathryn
K
Guinta
Manuel G
MG
Afable
Mikkael A
MA
Sekeres
Richard A
RA
Padgett
Ramon V
RV
Tiu
Jaroslaw P
JP
Maciejewski
D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007951:Leukemia, Myeloid / Q000175:diagnosis / Q000235:genetics / Q000401:mortality; D008297:Male; D009154:Mutation; D059645:Mutation Rate; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000235:genetics / Q000401:mortality; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D012326:RNA Splicing / Q000235:genetics*; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics* / Q000378:metabolism; D012261:Ribonucleoproteins / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D000068103:Serine-Arginine Splicing Factors; D017381:Spliceosomes / Q000235:genetics / Q000378:metabolism; D000072668:Splicing Factor U2AF
D009687:Nuclear Proteins; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; D012261:Ribonucleoproteins; C112491:SF3B1 protein, human; D000072668:Splicing Factor U2AF; C076753:U2AF1 protein, human; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors