BCL-6 mutations in normal germinal center B cells: Evidence of somatic hypermutation acting outside Ig loci

DOI Web Site 被引用文献10件
  • Laura Pasqualucci
    Departments of Pathology and Genetics and Development, Columbia University, New York, NY 10032; Servizio di Ematologia, Istituto di Scienze Mediche, Universita’ di Milano, Ospedale Maggiore Istituto di Ricoveroe Cura a Carattere Scientifico, Milan 20122, Italy; Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; and Institute of Genetics, University of Cologne, Cologne 50931, Germany
  • Anna Migliazza
    Departments of Pathology and Genetics and Development, Columbia University, New York, NY 10032; Servizio di Ematologia, Istituto di Scienze Mediche, Universita’ di Milano, Ospedale Maggiore Istituto di Ricoveroe Cura a Carattere Scientifico, Milan 20122, Italy; Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; and Institute of Genetics, University of Cologne, Cologne 50931, Germany
  • Nicola Fracchiolla
  • Christopher William
    Departments of Pathology and Genetics and Development, Columbia University, New York, NY 10032; Servizio di Ematologia, Istituto di Scienze Mediche, Universita’ di Milano, Ospedale Maggiore Istituto di Ricoveroe Cura a Carattere Scientifico, Milan 20122, Italy; Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; and Institute of Genetics, University of Cologne, Cologne 50931, Germany
  • Antonino Neri
  • Luca Baldini
  • R. S. K. Chaganti
    Departments of Pathology and Genetics and Development, Columbia University, New York, NY 10032; Servizio di Ematologia, Istituto di Scienze Mediche, Universita’ di Milano, Ospedale Maggiore Istituto di Ricoveroe Cura a Carattere Scientifico, Milan 20122, Italy; Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; and Institute of Genetics, University of Cologne, Cologne 50931, Germany
  • Ulf Klein
    Departments of Pathology and Genetics and Development, Columbia University, New York, NY 10032; Servizio di Ematologia, Istituto di Scienze Mediche, Universita’ di Milano, Ospedale Maggiore Istituto di Ricoveroe Cura a Carattere Scientifico, Milan 20122, Italy; Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; and Institute of Genetics, University of Cologne, Cologne 50931, Germany
  • Ralf Küppers
    Departments of Pathology and Genetics and Development, Columbia University, New York, NY 10032; Servizio di Ematologia, Istituto di Scienze Mediche, Universita’ di Milano, Ospedale Maggiore Istituto di Ricoveroe Cura a Carattere Scientifico, Milan 20122, Italy; Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; and Institute of Genetics, University of Cologne, Cologne 50931, Germany
  • Klaus Rajewsky
    Departments of Pathology and Genetics and Development, Columbia University, New York, NY 10032; Servizio di Ematologia, Istituto di Scienze Mediche, Universita’ di Milano, Ospedale Maggiore Istituto di Ricoveroe Cura a Carattere Scientifico, Milan 20122, Italy; Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; and Institute of Genetics, University of Cologne, Cologne 50931, Germany
  • Riccardo Dalla-Favera
    Departments of Pathology and Genetics and Development, Columbia University, New York, NY 10032; Servizio di Ematologia, Istituto di Scienze Mediche, Universita’ di Milano, Ospedale Maggiore Istituto di Ricoveroe Cura a Carattere Scientifico, Milan 20122, Italy; Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; and Institute of Genetics, University of Cologne, Cologne 50931, Germany

説明

<jats:p>The molecular mechanism involved in the process of antigen-driven somatic hypermutation of Ig genes is unknown, but it is commonly believed that this mechanism is restricted to the Ig loci. B cell lymphomas commonly display multiple somatic mutations clustering in the 5′-regulatory region of BCL-6, a proto-oncogene encoding for a POZ/Zinc finger transcriptional repressor expressed in germinal center (GC) B cells and required for GC formation. To determine whether BCL-6 mutations represent a tumor-associated phenomenon or reflect a physiologic mechanism, we screened single human tonsillar GC B cells for mutations occurring in the BCL-6 5′-noncoding region and in the Ig variable heavy chain sequences. Thirty percent of GC B cells, but not naive B cells, displayed mutations in the 742 bp region analyzed within the first intron of BCL-6 (overall frequency: 5 × 10<jats:sup>−4</jats:sup>/bp). Accordingly, an expanded survey in lymphoid malignancies showed that BCL-6 mutations are restricted to B cell tumors displaying GC or post-GC phenotype and carrying mutated Ig variable heavy chain sequences. These results indicate that the somatic hypermutation mechanism active in GC B cells physiologically targets non-Ig sequences.</jats:p>

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