BCL6 is regulated by p53 through a response element frequently disrupted in B-cell non-Hodgkin lymphoma.

The BCL6 transcriptional repressor mediates survival, proliferation, and differentiation blockade of B cells during the germinal-center reaction and is frequently misregulated in B-cell non-Hodgkin lymphoma (BNHL). The p53 tumor-suppressor gene is central to tumorigenesis. Microarray analysis identified BCL6 as a primary target of p53. The BCL6 intron 1 contains a region in which 3 types of genetic alterations are frequent in BNHL: chromosomal translocations, point mutations, and internal deletions. We therefore defined it as TMDR (translocations, mutations, and deletions region). The BCL6 gene contains a p53 response element (p53RE) residing within the TMDR. This p53RE contains a motif known to be preferentially targeted by somatic hypermutation. This p53RE is evolutionarily conserved only in primates. The p53 protein binds to this RE in vitro and in vivo. Reporter assays revealed that the BCL6 p53RE can confer p53-dependent transcriptional activation. BCL6 mRNA and protein levels increased after chemotherapy/radiotherapy in human but not in murine tissues. The increase in BCL6 mRNA levels was attenuated by the p53 inhibitor PFT-alpha. Thus, we define the BCL6 gene as a new p53 target, regulated through a RE frequently disrupted in BNHL.

[1]  Qiong Shen,et al.  Deregulated BCL6 expression recapitulates the pathogenesis of human diffuse large B cell lymphomas in mice. , 2005, Cancer cell.

[2]  Ryan T. Phan,et al.  The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells , 2004, Nature.

[3]  J. Licht,et al.  Specific peptide interference reveals BCL6 transcriptional and oncogenic mechanisms in B-cell lymphoma cells , 2004, Nature Medicine.

[4]  David L. Jaye,et al.  MTA3 and the Mi-2/NuRD Complex Regulate Cell Fate during B Lymphocyte Differentiation , 2004, Cell.

[5]  D. Felsher,et al.  The human BCL6 transgene promotes the development of lymphomas in the mouse. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Ash A. Alizadeh,et al.  Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. , 2004, The New England journal of medicine.

[7]  J. Martinez-Climent,et al.  Bcl-6 mutation status provides clinically valuable information in early-stage B-cell chronic lymphocytic leukemia , 2004, Leukemia.

[8]  R. Gentleman,et al.  Gene expression profile of adult T-cell acute lymphocytic leukemia identifies distinct subsets of patients with different response to therapy and survival. , 2004, Blood.

[9]  A. Dent,et al.  Transcriptional repressor BCL-6 immortalizes germinal center-like B cells in the absence of p53 function , 2004, Oncogene.

[10]  A. Scarpa,et al.  Primary mediastinal B-cell lymphoma: hypermutation of the BCL6 gene targets motifs different from those in diffuse large B-cell and follicular lymphomas. , 2004, Haematologica.

[11]  F. Watzinger,et al.  Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using ‘real-time’ quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR) – a Europe against cancer program , 2003, Leukemia.

[12]  F. Jardin,et al.  Intronic BCL-6 mutations are preferentially targeted to the translocated allele in t(3;14)(q27;q32) non-Hodgkin B-cell lymphoma. , 2003, Blood.

[13]  Takashi Akasaka,et al.  BCL6 gene translocation in follicular lymphoma: a harbinger of eventual transformation to diffuse aggressive lymphoma. , 2003, Blood.

[14]  T. Kurosu,et al.  BCL6 overexpression prevents increase in reactive oxygen species and inhibits apoptosis induced by chemotherapeutic reagents in B-cell lymphoma cells , 2003, Oncogene.

[15]  I. Lossos,et al.  The BCL6 gene in B-cell lymphomas with 3q27 translocations is expressed mainly from the rearranged allele irrespective of the partner gene , 2003, Leukemia.

[16]  N. Harris,et al.  BCL-6 expression predicts improved survival in patients with primary central nervous system lymphoma. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[17]  M. Oren,et al.  The p53-Mdm2 module and the ubiquitin system. , 2003, Seminars in cancer biology.

[18]  A. Naganuma,et al.  Negative autoregulation of BCL-6 is bypassed by genetic alterations in diffuse large B cell lymphomas , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Xin Lu,et al.  Live or let die: the cell's response to p53 , 2002, Nature Reviews Cancer.

[20]  J. Ott,et al.  The p53MH algorithm and its application in detecting p53-responsive genes , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[21]  D. Schatz,et al.  Somatic Hypermutation of Immunoglobulin Genes Merging Mechanisms for Genetic Diversity , 2002, Cell.

[22]  M. Piris,et al.  A short mutational hot spot in the first intron of BCL-6 is associated with increased BCL-6 expression and with longer overall survival in large B-cell lymphomas. , 2002, The American journal of pathology.

[23]  H. Ohno,et al.  Immunoglobulin (Ig)/BCL6 versus non-Ig/BCL6 gene fusion in diffuse large B-cell lymphoma corresponds to a high- versus low-level expression of BCL6 mRNA. , 2002, Blood.

[24]  René Bernards,et al.  A senescence rescue screen identifies BCL6 as an inhibitor of anti-proliferative p19(ARF)-p53 signaling. , 2002, Genes & development.

[25]  Y. Furukawa,et al.  The human programmed cell death-2 (PDCD2) gene is a target of BCL6 repression: Implications for a role of BCL6 in the down-regulation of apoptosis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[26]  G. Gaidano,et al.  Point mutations of the BCL-6 gene: clinical and prognostic correlation in B-diffuse large cell lymphoma , 2002, Leukemia.

[27]  T. Honjo,et al.  Molecular mechanism of class switch recombination: linkage with somatic hypermutation. , 2002, Annual review of immunology.

[28]  R. Iggo,et al.  Chromatin immunoprecipitation analysis fails to support the latency model for regulation of p53 DNA binding activity in vivo , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[29]  I. Lossos,et al.  Re: Akasaka, H., et al., Molecular anatomy of BCL6 translocations revealed by long-distance polymerase chain reaction-based assays. Cancer Res., 60: 2335-2341, 2000. , 2001, Cancer research.

[30]  T. Burns,et al.  Tissue specific expression of p53 target genes suggests a key role for KILLER/DR5 in p53-dependent apoptosis in vivo , 2001, Oncogene.

[31]  C. Ziske,et al.  Effects of adenoviral wild-type p53 gene transfer in p53 -mutated lymphoma cells , 2001, Cancer Gene Therapy.

[32]  G. Getz,et al.  DNA microarrays identification of primary and secondary target genes regulated by p53 , 2001, Oncogene.

[33]  H. Stein,et al.  Analysis of BCL-6 mutations in classic Hodgkin disease of the B- and T-cell type. , 2001, Blood.

[34]  L. Staudt,et al.  BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. , 2000, Immunity.

[35]  I. Lossos,et al.  Higher-grade transformation of follicle center lymphoma is associated with somatic mutation of the 5' noncoding regulatory region of the BCL-6 gene. , 2000, Blood.

[36]  H. Ohno,et al.  Molecular anatomy of BCL6 translocations revealed by long-distance polymerase chain reaction-based assays. , 2000, Cancer research.

[37]  L. Pasqualucci,et al.  Distribution and pattern of BCL-6 mutations throughout the spectrum of B-cell neoplasia. , 2000, Blood.

[38]  Y. Nakamura.  Internal deletions within the BCL6 gene in B-cell non-Hodgkin's lymphoma. , 2000, Leukemia & lymphoma.

[39]  Y. Taya,et al.  Activation of p53 in MDM2-overexpressing cells through phosphorylation. , 1999, Biochemical and biophysical research communications.

[40]  R. Gascoyne,et al.  Bcl-6 and Bcl-2 protein expression in diffuse large B-cell lymphoma and follicular lymphoma: correlation with 3q27 and 18q21 chromosomal abnormalities. , 1999, Human pathology.

[41]  Yuichi Nakamura,et al.  Analysis of internal deletions within the BCL6 gene in B‐cell non‐Hodgkin's lymphoma , 1999, British journal of haematology.

[42]  P. Isaacson,et al.  Nonimmunoglobulin gene hypermutation in germinal center B cells. , 1999, Blood.

[43]  J Hermans,et al.  Clinical relevance of BCL2, BCL6, and MYC rearrangements in diffuse large B-cell lymphoma. , 1998, Blood.

[44]  P. Lipsky,et al.  Somatic hypermutation of human immunoglobulin heavy chain genes: targeting of RGYW motifs on both DNA strands , 1998, European journal of immunology.

[45]  L. Pasqualucci,et al.  BCL-6 mutations in normal germinal center B cells: evidence of somatic hypermutation acting outside Ig loci. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[46]  S. Iida,et al.  Heterologous promoters fused to BCL6 by chromosomal translocations affecting band 3q27 cause its deregulated expression during B-cell differentiation. , 1998, Blood.

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

[48]  D. Leprince,et al.  Small deletions occur in highly conserved regions of the LAZ3/BCL6 major translocation cluster in one case of non-Hodgkin's lymphoma without 3q27 translocation , 1997, Oncogene.

[49]  Philippe Dessen,et al.  Further characterisation of the p53 responsive element – identification of new candidate genes for trans-activation by p53 , 1997, Oncogene.

[50]  J. Danska,et al.  V(D)J recombination activates a p53-dependent DNA damage checkpoint in scid lymphocyte precursors. , 1996, Genes & development.

[51]  S. Pittaluga,et al.  BCL‐6 EXPRESSION IN REACTIVE LYMPHOID TISSUE AND IN B‐CELL NON‐HODGKIN'S LYMPHOMAS , 1996, The Journal of pathology.

[52]  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.

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

[54]  V. Rotter,et al.  The DNA binding activity of wild type p53 is modulated by blocking its various antigenic epitopes. , 1995, Oncogene.

[55]  K. Kohn,et al.  p53 gene mutations are associated with decreased sensitivity of human lymphoma cells to DNA damaging agents. , 1994, Cancer research.

[56]  M. Ladanyi,et al.  Rearrangement of the bcl-6 gene as a prognostic marker in diffuse large-cell lymphoma. , 1994, The New England journal of medicine.

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

[58]  P. Hainaut,et al.  Analysis of p53 quaternary structure in relation to sequence-specific DNA binding. , 1994, Oncogene.

[59]  M. Oren,et al.  Wild type p53 can mediate sequence-specific transactivation of an internal promoter within the mdm2 gene. , 1993, Oncogene.

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

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

[62]  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.

[63]  K. Kinzler,et al.  Definition of a consensus binding site for p53 , 1992, Nature Genetics.

[64]  A. Levine,et al.  The p53 tumour suppressor gene , 1991, Nature.

[65]  E. Myers,et al.  Basic local alignment search tool. , 1990, Journal of molecular biology.

[66]  O. Halevy,et al.  Conditional inhibition of transformation and of cell proliferation by a temperature-sensitive mutant of p53 , 1990, Cell.

[67]  What Are All Those Funny Symbols in a Blast Printout? Blast = Basic Local Alignment Search Tool , 2022 .