BCL-6 gene mutations in posttransplantation lymphoproliferative disorders predict response to therapy and clinical outcome.

Posttransplantation lymphoproliferative disorders (PT-LPDs) represent a heterogeneous group of Epstein-Barr virus-associated lymphoid proliferations that arise in immunosuppressed transplant recipients. Some of these lesions regress after a reduction in immunosuppressive therapy, whereas some progress despite aggressive therapy. Morphological, immunophenotypic, and immunogenotypic criteria have not been useful in predicting clinical outcome. Although structural alterations in oncogenes and/or tumor suppressor genes identified in some PT-LPDs correlate with a poor clinical outcome, the presence of these alterations has not been a consistently useful predictor of lesion regression after reduction of immunosuppression. We examined 57 PT-LPD lesions obtained from 36 solid organ transplant recipients for the presence of mutations in the BCL-6 proto-oncogene using single-strand conformation polymorphism and sequence analysis, followed by correlation with histopathologic classification and clinical outcome, which was known in 33 patients. BCL-6 gene mutations were identified in 44% of the specimens and in 44% of the patients; none were identified in the cases classified as plasmacytic hyperplasia. However, mutations were present in 43% of the polymorphic lesions and 90% of the PT-LPDs diagnosed as non-Hodgkin's lymphoma or multiple myeloma. BCL-6 gene mutations predicted shorter survival and refractoriness to reduced immunosuppression and/or surgical excision. Our results suggest that the BCL-6 gene structure is a reliable indicator for the division of PT-LPDs into the biological categories of hyperplasia and malignant lymphoma, of which only the former can regress on immune reconstitution. The presence of BCL-6 gene mutations may be a useful clinical marker to determine whether reduction in immunosuppression should be attempted or more aggressive therapy should be instituted.

[1]  E. Cesarman,et al.  The morphologic and molecular genetic categories of posttransplantation lymphoproliferative disorders are clinically relevant , 1998, Cancer.

[2]  E. Cesarman,et al.  Epstein-Barr virus latent membrane protein-1 oncogene deletion in post-transplantation lymphoproliferative disorders. , 1997, The American journal of pathology.

[3]  P. Pandolfi,et al.  The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation , 1997, Nature Genetics.

[4]  G. Gaidano,et al.  Frequent mutation of the 5' noncoding region of the BCL-6 gene in acquired immunodeficiency syndrome-related non-Hodgkin's lymphomas. , 1997, Blood.

[5]  L. Staudt,et al.  Control of inflammation, cytokine expression, and germinal center formation by BCL-6. , 1997, Science.

[6]  N. Harris,et al.  Posttransplant lymphoproliferative disorders: summary of Society for Hematopathology Workshop. , 1997, Seminars in diagnostic pathology.

[7]  E. Cesarman,et al.  Molecular pathology of posttransplantation lymphoproliferative disorders. , 1997, Seminars in diagnostic pathology.

[8]  R S Chaganti,et al.  BCL-6, a POZ/zinc-finger protein, is a sequence-specific transcriptional repressor. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[9]  L. Staudt,et al.  BCL-6 expression during B-cell activation. , 1996, Blood.

[10]  L. Staudt,et al.  Transcriptional repression by the proto-oncogene BCL-6. , 1996, Oncogene.

[11]  S. Pileri,et al.  Monoclonal antibodies PG-B6a and PG-B6p recognize, respectively, a highly conserved and a formol-resistant epitope on the human BCL-6 protein amino-terminal region. , 1996, The American journal of pathology.

[12]  K. Offit,et al.  Frequent somatic hypermutation of the 5' noncoding region of the BCL6 gene in B-cell lymphoma. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[13]  D. Leprince,et al.  The LAZ3/BCL6 oncogene encodes a sequence-specific transcriptional inhibitor: a novel function for the BTB/POZ domain as an autonomous repressing domain. , 1995, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[14]  R. Chaganti,et al.  Chromosomal translocations cause deregulated BCL6 expression by promoter substitution in B cell lymphoma. , 1995, The EMBO journal.

[15]  E. Pescarmona,et al.  Analysis of the BCL‐6 gene configuration in diffuse B‐cell non‐Hodgkin's lymphomas and Hodgkin's disease , 1995, The Journal of pathology.

[16]  S. Mori,et al.  BCL-6 gene product, a 92- to 98-kD nuclear phosphoprotein, is highly expressed in germinal center B cells and their neoplastic counterparts. , 1995, Blood.

[17]  K. Offit,et al.  BCL-6 protein is expressed in germinal-center B cells. , 1995, Blood.

[18]  Yi Fang Liu,et al.  Molecular genetic analysis demonstrates that multiple posttransplantation lymphoproliferative disorders occurring in one anatomic site in a single patient represent distinct primary lymphoid neoplasms , 1995, Cancer.

[19]  E. Jaffe,et al.  Analysis of LAZ3 (BCL-6) status in B-cell non-Hodgkin's lymphomas: results of rearrangement and gene expression studies and a mutational analysis of coding region sequences. , 1995, Blood.

[20]  Yi Fang Liu,et al.  Posttransplantation lymphoproliferative disorders frequently contain type A and not type B Epstein-Barr virus. , 1995, Blood.

[21]  S. Pileri,et al.  A specific monoclonal antibody (PG-B6) detects expression of the BCL-6 protein in germinal center B cells. , 1995, The American journal of pathology.

[22]  E. Cesarman,et al.  Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders. , 1995, Blood.

[23]  D. Shibata,et al.  Rearrangements of the BCL-6 Gene in Acquired Immunodeficiency Syndrome-Associated Non-Hodgkin's Lymphoma: Association With Diffuse Large-Cell Subtype , 1994 .

[24]  A. Rossi,et al.  LAZ3 rearrangements in non-Hodgkin's lymphoma: correlation with histology, immunophenotype, karyotype, and clinical outcome in 217 patients. , 1994, Blood.

[25]  K. Offit,et al.  Rearrangements of the BCL6 gene in diffuse large cell non-Hodgkin's lymphoma. , 1994, Blood.

[26]  N. Aoki,et al.  Gene involved in the 3q27 translocation associated with B-cell lymphoma, BCL5, encodes a Krüppel-like zinc-finger protein. , 1994, Blood.

[27]  K. Rajewsky,et al.  Tracing B cell development in human germinal centres by molecular analysis of single cells picked from histological sections. , 1993, The EMBO journal.

[28]  H. Tilly,et al.  Cloning of a breakpoint cluster region at band 3q27 involved in human non‐Hodgkin's lymphoma , 1993, Genes, chromosomes & cancer.

[29]  K Offit,et al.  Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma. , 1993, Science.

[30]  R. Michler,et al.  Management of lymphoproliferative disorders after cardiac transplantation. , 1993, The Annals of thoracic surgery.

[31]  H. Tilly,et al.  LAZ3, a novel zinc–finger encoding gene, is disrupted by recurring chromosome 3q27 translocations in human lymphomas , 1993, Nature Genetics.

[32]  R. Espinosa,et al.  Identification of the gene associated with the recurring chromosomal translocations t(3;14)(q27;q32) and t(3;22)(q27;q11) in B-cell lymphomas. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[33]  D. Dunn,et al.  Posttransplant lymphoproliferative disorders , 1991 .

[34]  J. Locker,et al.  Molecular genetic analysis of lymphoid tumors arising after organ transplantation. , 1989, The American journal of pathology.

[35]  Shirley A. Miller,et al.  A simple salting out procedure for extracting DNA from human nucleated cells. , 1988, Nucleic acids research.

[36]  J. Locker,et al.  The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppression. , 1988, The American journal of pathology.

[37]  J. Sklar,et al.  Clonal analysis of transplant-associated lymphoproliferations based on the structure of the genomic termini of the Epstein-Barr virus. , 1988, Blood.

[38]  J. Sklar,et al.  LYMPHOPROLIFERATIVE DISORDERS IN CARDIAC TRANSPLANT RECIPIENTS ARE MULTICLONAL LYMPHOMAS , 1984, The Lancet.

[39]  T. Starzl,et al.  REVERSIBILITY OF LYMPHOMAS AND LYMPHOPROLIFERATIVE LESIONS DEVELOPING UNDER CYCLOSPORIN-STEROID THERAPY , 1984, The Lancet.

[40]  R. Warnke,et al.  Monoclonality of lymphoproliferative lesions in cardiac-transplant recipients. Clonal analysis based on immunoglobulin-gene rearrangements. , 1984, The New England journal of medicine.

[41]  J. Rosai,et al.  Polymorphic diffuse B-cell hyperplasias and lymphomas in renal transplant recipients. , 1981, Cancer research.