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Analysis of BCL-6, CD95, PIM1, RHO/TTF and PAX5 mutations in splenic and nodal marginal zone B-cell lymphomas suggests a particular B-cell origin

Leukemia volume 21, pages 1821–1824 (2007)Cite this article

Several lymphoma entities have been recognized in the World Health Organization (WHO) classification of hematological malignancies, including splenic marginal zone lymphoma (SMZL) with or without villous lymphocytes and nodal marginal zone lymphoma (NMZL) with or without monocytoid B cells. Although this classification led to a better morphologic recognition of these lymphoma entities, several questions are still debated such as the exact situation of the cell at the origin of the disease within the B-cell differentiation pathway, especially its transit through germinal center (GC) and the mechanisms involved in lymphomagenesis.

SMZL and NMZL may have a common origin in the marginal B-cell compartment of lymphoid organ. However, the marginal zone contains a variety of B cells, both early antibody-forming cells and memory B cells in response to T-dependent and T-independent antigens. And the exact cell at the origin of these lymphomas remains unknown. In a previous molecular analysis, we reported that the IgVH mutational pattern of SMZL and NMZL is different from that described in usual GC cells.1 Evidence of antigen encounter (as shown by the presence of somatic mutation) but coexisting with a marked proportion of clones without any affinity maturation characteristics has suggested that B cells implicated in T-cell-independent immune response could represent the cell of origin of these lymphomas.1 Following this hypothesis and to better understand the mechanisms of lymphomagenesis, we decided to explore the somatic mutations in other genes. The somatic hypermutation mechanism (SHM) in normal B-cell differentiation has been clearly demonstrated to target non-Ig genes, such as BCL-6, CD95 and CD79 in normal GC B cells.2, 3, 4 Mutation of these genes has also been reported in the vast majority of mature B-cell malignancies4, 5, 6 (20–50% of lymphoma cases for BCL-6 oncogene, 2.5–60% for the CD95 gene and 78–96% for the CD79 gene). Interestingly, most of these cases represent GC-derived lymphomas and BCL6 and CD95 mutations are likely to reflect mutations acquired during GC reaction. In addition, aberrant SHM occurring in the 5′ sequence of several oncogenes might also contribute to B-cell lymphomagenesis by deregulating gene expression. These aberrant somatic mutations were identified in some lymphoma entities, especially diffuse large B-cell lymphomas (DLBCL), where several oncogenes including PIM-1, PAX5, Rho/TTF and c-MYC were found to be mutated7 independently of chromosomal translocations. In contrast to CD79, CD95, BCL-6 and IgVH genes, these mutations do not occur in normal GC B cells, suggesting a dysfunction of the SHM process in several lymphoma entities.

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Acknowledgements

This work was supported by a grant from la Ligue contre le Cancer (comité départemental du Rhône).

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Authors and Affiliations

  1. Service d'Anatomie Pathologique, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre Bénite, France

    A Traverse-Glehen & F Berger

  2. EA 3737, ‘Pathologie des Cellules Lymphoides’, Université Lyon 1, Lyon, France

    A Traverse-Glehen, A Verney, L Baseggio, P Felman, E Callet-Bauchu, C Thieblemont, M Ffrench, J-P Magaud, B Coiffier, F Berger & G Salles

  3. Laboratoire d'Hématologie, Centre Hospitalier Lyon Sud, Pierre Bénite, France

    L Baseggio, P Felman, E Callet-Bauchu, M Ffrench & J-P Magaud

  4. Service d'Hématologie, Centre Hospitalier Lyon Sud, Pierre Bénite, France

    C Thieblemont, B Coiffier & G Salles

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  1. A Traverse-Glehen
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Traverse-Glehen, A., Verney, A., Baseggio, L. et al. Analysis of BCL-6, CD95, PIM1, RHO/TTF and PAX5 mutations in splenic and nodal marginal zone B-cell lymphomas suggests a particular B-cell origin. Leukemia 21, 1821–1824 (2007). https://doi.org/10.1038/sj.leu.2404706

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