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

DOI PDF PubMed 被引用文献23件 オープンアクセス
  • Hideki Makishima
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
  • Valeria Visconte
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
  • Hirotoshi Sakaguchi
    Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan; and
  • Anna M. Jankowska
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
  • Sarah Abu Kar
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
  • Andres Jerez
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
  • Bartlomiej Przychodzen
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
  • Manoj Bupathi
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
  • Kathryn Guinta
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
  • Manuel G. Afable
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
  • Mikkael A. Sekeres
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
  • Richard A. Padgett
    Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
  • Ramon V. Tiu
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
  • Jaroslaw P. Maciejewski
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;

書誌事項

公開日
2012-04-05
DOI
  • 10.1182/blood-2011-12-399774
公開者
American Society of Hematology

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<jats:title>Abstract</jats:title> <jats:p>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.</jats:p>

収録刊行物

  • Blood

    Blood 119 (14), 3203-3210, 2012-04-05

    American Society of Hematology

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