Stereotyped patterns of B-cell receptor in splenic marginal zone lymphoma

Antigen stimulation may be important for splenic marginal zone lymphoma pathogenesis. To address this hypothesis, the occurrence of stereotyped B-cell receptors was investigated in 133 SMZL (26 HCV+) compared with 4,414 HCDR3 sequences from public databases. Sixteen SMZL (12%) showed stereotyped BCR; 7 of 86 (8%) SMZL sequences retrieved from public databases also belonged to stereotyped HCDR3 subsets. Three categories of subsets were identified: i) "SMZL-specific subsets" (n=5), composed only of 12 SMZL (9 HCV-from our series); ii) "Non-Hodgkin’s lymphoma-like subsets" (n=5), comprising 5 SMZL (4 from our series) clustering with other indolent lymphomas; iii) “CLL-like subsets” (n=6), comprising 6 SMZL (3 from our series) that belonged to known CLL subsets (n=4) or clustered with public CLL sequences. Immunoglobulin 3D modeling of 3 subsets revealed similarities in antigen binding regions not limited to HCDR3. Overall, data suggest that the pathogenesis of splenic marginal zone lymphoma may involve also HCV-unrelated epitopes or an antigenic trigger common to other indolent lymphomas.

[1]  Sigrid Stroobants,et al.  Revised response criteria for malignant lymphoma. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  J. Delabie,et al.  Splenic marginal zone lymphoma with villous lymphocytes shows on-going immunoglobulin gene mutations. , 2003, The American journal of pathology.

[3]  E. Campo,et al.  Analysis of the IgV(H) somatic mutations in splenic marginal zone lymphoma defines a group of unmutated cases with frequent 7q deletion and adverse clinical course. , 2002, Blood.

[4]  S. Swerdlow,et al.  Splenic marginal zone lymphomas appear to originate from different B cell types. , 2002, The American journal of pathology.

[5]  D. Oscier,et al.  V(H) gene analysis of splenic marginal zone lymphomas reveals diversity in mutational status and initiation of somatic mutation in vivo. , 2002, Blood.

[6]  Nathan A. Baker,et al.  Electrostatics of nanosystems: Application to microtubules and the ribosome , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[7]  C. Pascutto,et al.  Splenic marginal zone lymphoma: Clinical clustering of immunoglobulin heavy chain repertoires. , 2009, Blood cells, molecules & diseases.

[8]  Nikolaos Laoutaris,et al.  Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis. , 2007, Blood.

[9]  P. Isaacson,et al.  Analysis of immunoglobulin genes in splenic marginal zone lymphoma suggests ongoing mutation. , 1998, Human pathology.

[10]  M. Lefranc.  IMGT, the international ImMunoGeneTics information system for Immunoinformatics. Methods for querying IMGT databases, tools, and Web resources in the context of immunoinformatics. , 2008, Methods in molecular biology.

[11]  S. Malek,et al.  Chronic Lymphocytic Leukemia , 2019, Methods in Molecular Biology.

[12]  F. Stevenson,et al.  Tumor cells of hairy cell leukemia express multiple clonally related immunoglobulin isotypes via RNA splicing. , 2001, Blood.

[13]  G. Salles,et al.  Analysis of VH genes in marginal zone lymphoma reveals marked heterogeneity between splenic and nodal tumors and suggests the existence of clonal selection. , 2005, Haematologica.

[14]  R. Doolittle,et al.  A simple method for displaying the hydropathic character of a protein. , 1982, Journal of molecular biology.

[15]  D. Oscier,et al.  Splenic lymphoma with villous lymphocytes involves B cells with extensively mutated Ig heavy chain variable region genes. , 1995, Blood.

[16]  J. Delabie,et al.  Mutation analysis of the rearranged immunoglobulin heavy chain genes of marginal zone cell lymphomas indicates an origin from different marginal zone B lymphocyte subsets. , 1998, Blood.

[17]  Nikolaos Laoutaris,et al.  Over 20% of patients with chronic lymphocytic leukemia carry stereotyped receptors: Pathogenetic implications and clinical correlations. , 2006, Blood.

[18]  Rodrigo Lopez,et al.  Clustal W and Clustal X version 2.0 , 2007, Bioinform..

[19]  X. Mariette,et al.  Splenic lymphoma with villous lymphocytes, associated with type II cryoglobulinemia and HCV infection: a new entity? , 2005, Blood.

[20]  E. Iannitto,et al.  Splenic marginal zone lymphoma: a prognostic model for clinical use. , 2006, Blood.

[21]  A. Salar,et al.  Splenic marginal zone lymphoma proposals for a revision of diagnostic, staging and therapeutic criteria , 2008, Leukemia.

[22]  Francesco Bertoni,et al.  Stereotyped B-Cell Receptor Is an Independent Risk Factor of Chronic Lymphocytic Leukemia Transformation to Richter Syndrome , 2009, Clinical Cancer Research.

[23]  A. Lesk,et al.  Standard conformations for the canonical structures of immunoglobulins. , 1997, Journal of molecular biology.

[24]  Steven L. Allen,et al.  Multiple Distinct Sets of Stereotyped Antigen Receptors Indicate a Role for Antigen in Promoting Chronic Lymphocytic Leukemia , 2004, The Journal of experimental medicine.

[25]  T. Blundell,et al.  Comparative protein modelling by satisfaction of spatial restraints. , 1993, Journal of molecular biology.

[26]  Paolo Marcatili,et al.  PIGS: automatic prediction of antibody structures , 2008, Bioinform..

[27]  K. Stamatopoulos,et al.  Immunoglobulin Heavy- And Light-chain Repertoire in Splenic Marginal Zone Lymphoma , 2004, Molecular medicine.