Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis

Blood. 2012 Apr 5;119(14):3203-10. doi: 10.1182/blood-2011-12-399774. Epub 2012 Feb 9.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Transformation, Neoplastic / genetics*
  • Female
  • Genetic Association Studies
  • Humans
  • Leukemia, Myeloid / diagnosis
  • Leukemia, Myeloid / genetics
  • Leukemia, Myeloid / mortality
  • Male
  • Mutation Rate
  • Mutation*
  • Myelodysplastic Syndromes / diagnosis
  • Myelodysplastic Syndromes / genetics
  • Myelodysplastic Syndromes / mortality
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Prognosis
  • RNA Splicing / genetics*
  • RNA Splicing Factors
  • Ribonucleoprotein, U2 Small Nuclear / genetics*
  • Ribonucleoprotein, U2 Small Nuclear / metabolism
  • Ribonucleoproteins / genetics*
  • Ribonucleoproteins / metabolism
  • Sequence Alignment
  • Serine-Arginine Splicing Factors
  • Spliceosomes / genetics
  • Spliceosomes / metabolism
  • Splicing Factor U2AF


  • Nuclear Proteins
  • Phosphoproteins
  • RNA Splicing Factors
  • Ribonucleoprotein, U2 Small Nuclear
  • Ribonucleoproteins
  • SF3B1 protein, human
  • Splicing Factor U2AF
  • U2AF1 protein, human
  • SRSF2 protein, human
  • Serine-Arginine Splicing Factors