Control of inflammation, cytokine expression, and germinal center formation by BCL-6.

The gene encoding the BCL-6 transcriptional repressor is frequently translocated and mutated in diffuse large cell lymphoma. Mice with a disrupted BCL-6 gene developed myocarditis and pulmonary vasculitis, had no germinal centers, and had increased expression of T helper cell type 2 cytokines. The BCL-6 DNA recognition motif resembled sites bound by the STAT (signal transducers and activators of transcription) transcription factors, which mediate cytokine signaling. BCL-6 could repress interleukin-4 (IL-4)-induced transcription when bound to a site recognized by the IL-4-responsive transcription factor Stat6. Thus, dysregulation of STAT-responsive genes may underlie the inflammatory disease in BCL-6-deficient mice and participate in lymphoid malignancies.

[1]  David D. Chaplin,et al.  Role of Lymphotoxin and the Type I TNF Receptor in the Formation of Germinal Centers , 1996, Science.

[2]  M. Kaplan,et al.  Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. , 1996, Immunity.

[3]  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.

[4]  J. Darnell,et al.  Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. , 1995, Annual review of biochemistry.

[5]  C. Schindler,et al.  STF‐IL‐4: a novel IL‐4‐induced signal transducing factor. , 1994, The EMBO journal.

[6]  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.

[7]  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.

[8]  W. Paul,et al.  Acquisition of lymphokine-producing phenotype by CD4+ T cells. , 1994, Annual review of immunology.

[9]  G. Kelsoe,et al.  In Situ Studies of the Primary Immune Response to ( 4-hydroxy-3-nitrophenyl ) acetyl . II . A Common Clonal Origin for Periarteriolar Lymphoid Sheath-associated Foci and Germinal Centers , 2003 .

[10]  J. D. Capra,et al.  Analysis of somatic mutation in five B cell subsets of human tonsil , 1994, The Journal of experimental medicine.

[11]  E. Rieber,et al.  Allergy‐associated Iϵ and Fcϵ receptor II (CD23b) genes activated via binding of an interleukin‐4‐induced transcription factor to a novel responsive element , 1993 .

[12]  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.

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

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

[15]  S. Akira,et al.  Essential role of Stat6 in IL-4 signalling , 1996, Nature.

[16]  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.

[17]  R. Coffman,et al.  Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. , 1986, Journal of immunology.

[18]  W. Schaffner,et al.  Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells. , 1989, Nucleic acids research.

[19]  R. Bronson,et al.  Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene , 1991, Cell.

[20]  Kenneth M. Murphy,et al.  Functional diversity of helper T lymphocytes , 1996, Nature.

[21]  N. Aoki,et al.  Recognition DNA sequence of a novel putative transcription factor, BCL6. , 1994, Biochemical and biophysical research communications.

[22]  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.

[23]  Martin Bachmann,et al.  Disruption of the murine IL-4 gene blocks Th2 cytokine responses , 1993, Nature.

[24]  G. Kollias,et al.  Immune and inflammatory responses in TNF alpha-deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response , 1996, The Journal of experimental medicine.

[25]  N. Zeleznik-Le,et al.  BCL6 encodes a sequence‐specific DNA‐binding Protein , 1995, Genes, chromosomes & cancer.

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

[27]  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.

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

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