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

Proceedings of the National Academy of Sciences of the United States of America - Tập 95 Số 20 - Trang 11816-11821 - 1998
Laura Pasqualucci1, Anna Migliazza1, Nicola Fracchiolla, Christopher William1, Antonino Neri, Luca Baldini, R. S. K. Chaganti1, Ulf Klein1, Ralf Küppers1, Klaus Rajewsky1, Riccardo Dalla‐Favera1
1Departments 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

Tóm tắt

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 × 10−4/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.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 95 Số 20

11816-11821

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