Differential Eµ enhancer activity and expression of BOB.1/OBF.1, Oct2, PU.1, and immunoglobulin in reactive B‐cell populations, B‐cell non‐Hodgkin lymphomas, and Hodgkin lymphomas

It has previously been demonstrated that in cultured and in situ tumour cells of classical Hodgkin lymphoma (cHL), the immunoglobulin (Ig) promoter is inactive and its transcription factors Oct2 and/or BOB.1/OBF.1 are down‐regulated. In this study, the analysis of these transcription factors has been extended to a broad spectrum of B‐cell malignancies and the findings have been related to the situation in normal B‐cells of various differentiation stages and to the expression of Ig. Furthermore, an additional Ig transcription factor, PU.1, recently described to be absent from cHL, and a further regulatory element of the Ig gene, the intronic Eµ enhancer, have been studied. BOB.1/OBF.1 and Oct2 were present in all B‐cells expressing Ig, whereas PU.1 proved to be absent from late B‐cell differentiation stages and from a subset of germinal centre B‐cells. Interestingly, there were several normal (eg germinal centre centroblasts and monocytoid B‐cells) and malignant B‐cell populations (eg a proportion of diffuse large B‐cell lymphomas, DLBCLs) that were Ig‐negative, despite their BOB.1/OBF.1 and Oct2 expression. This study further shows that absence of PU.1 alone, as well as inactivation of the intronic Eµ enhancer, is not sufficient to down‐regulate Ig transcription. Taken together, the simultaneous absence of PU.1, Oct2, and/or BOB.1/OBF.1 is unique to Hodgkin and Reed–Sternberg (HRS) cells and cannot be detected in normal B‐cell subsets or B‐cell non‐Hodgkin lymphomas (B‐NHLs). This supports the concept that the down‐regulation of Ig in cHL does not reflect a physiological situation, but a defect probably closely linked to the pathogenesis of cHL. Copyright © 2004 John Wiley & Sons, Ltd.

[1]  K. Rajewsky,et al.  Typing the histogenetic origin of the tumor cells of lymphocyte-rich classical Hodgkin's lymphoma in relation to tumor cells of classical and lymphocyte-predominance Hodgkin's lymphoma. , 2003, Cancer research.

[2]  C. Fellbaum,et al.  Expression patterns of transcription factors in progressively transformed germinal centers and Hodgkin lymphoma , 2003, Virchows Archiv.

[3]  Clifford S. Deutschman,et al.  Transcription , 2003, The Quran: Word List (Volume 3).

[4]  S. Hamilton-Dutoit,et al.  Loss of B cell identity correlates with loss of B cell-specific transcription factors in Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma , 2002, Oncogene.

[5]  H. Stein,et al.  Loss of PU.1 expression is associated with defective immunoglobulin transcription in Hodgkin and Reed-Sternberg cells of classical Hodgkin disease. , 2002, Blood.

[6]  Juan F. García,et al.  Analysis of Octamer-Binding Transcription Factors Oct2 and Oct1 and their coactivator BOB.1/OBF.1 in Lymphomas , 2002, Modern Pathology.

[7]  D. Hossfeld.  E.S. Jaffe, N.L. Harris, H. Stein, J.W. Vardiman (eds). World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues , 2002 .

[8]  B. Chapuis,et al.  Expression of transcription factors Pu.1, Spi‐B, Blimp‐1, BSAP and oct‐2 in normal human plasma cells and in multiple myeloma cells , 2002, British journal of haematology.

[9]  J. Delabie,et al.  The transcription factor PU.1, necessary for B-cell development is expressed in lymphocyte predominance, but not classical Hodgkin's disease. , 2001, The American journal of pathology.

[10]  P. Möller,et al.  Isotype-switched immunoglobulin genes with a high load of somatic hypermutation and lack of ongoing mutational activity are prevalent in mediastinal B-cell lymphoma. , 2001, Blood.

[11]  V. Diehl,et al.  Oct-2 and Bob-1 deficiency in Hodgkin and Reed Sternberg cells. , 2001, Cancer research.

[12]  H. Bujard,et al.  The B Lymphocyte-Specific Coactivator BOB.1/OBF.1 Is Required at Multiple Stages of B-Cell Development , 2001, Molecular and Cellular Biology.

[13]  H. Stein,et al.  Down-regulation of BOB.1/OBF.1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription. , 2001, Blood.

[14]  H. Singh,et al.  Regulation of B lymphocyte and macrophage development by graded expression of PU.1. , 2000, Science.

[15]  H. Stein,et al.  Hodgkin and reed-sternberg cells represent an expansion of a single clone originating from a germinal center B-cell with functional immunoglobulin gene rearrangements but defective immunoglobulin transcription. , 2000, Blood.

[16]  T. Wirth,et al.  The BOB.1 / OBF.1 co‐activator is essential for octamer‐dependent transcription in B cells , 2000, European journal of immunology.

[17]  H. Müller-Hermelink,et al.  Up-regulation of BOB.1/OBF.1 expression in normal germinal center B cells and germinal center-derived lymphomas. , 2000, The American journal of pathology.

[18]  H. Stein,et al.  Monocytoid B cells are distinct from splenic marginal zone cells and commonly derive from unmutated naive B cells and less frequently from postgerminal center B cells by polyclonal transformation. , 1999, Blood.

[19]  H. Stein,et al.  Hodgkin/Reed-Sternberg cells induce fibroblasts to secrete eotaxin, a potent chemoattractant for T cells and eosinophils. , 1999, Blood.

[20]  P. Matthias,et al.  Coactivator OBF-1 Makes Selective Contacts with Both the POU-Specific Domain and the POU Homeodomain and Acts as a Molecular Clamp on DNA , 1998, Molecular and Cellular Biology.

[21]  P. Matthias.  Lymphoid-specific transcription mediated by the conserved octamer site: who is doing what? , 1998, Seminars in immunology.

[22]  K. Rajewsky,et al.  Diffuse large cell lymphomas are derived from mature B cells carrying V region genes with a high load of somatic mutation and evidence of selection for antibody expression , 1997, European journal of immunology.

[23]  A. Rolink,et al.  B-cell-specif ic coactivator OBF-1/OCA-B/Bob1 required for immune response and germinal centre formation , 1996, Nature.

[24]  A. Feeney,et al.  Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. , 1996, The EMBO journal.

[25]  K. Rajewsky,et al.  Hodgkin and Reed-Sternberg cells in Hodgkin's disease represent the outgrowth of a dominant tumor clone derived from (crippled) germinal center B cells , 1996, The Journal of experimental medicine.

[26]  U. Storb,et al.  Pip, a novel IRF family member, is a lymphoid-specific, PU.1-dependent transcriptional activator. , 1995, Genes & development.

[27]  E. Scott,et al.  Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. , 1994, Science.

[28]  M. Klemsz,et al.  Hematopoietic lineage- and stage-restricted expression of the ETS oncogene family member PU.1. , 1993, Blood.

[29]  S. Pileri,et al.  Lymphotoxin, tumour necrosis factor and interleukin‐6 gene transcripts are present in Hodgkin and Reed‐Sternberg cells of most Hodgkin's disease cases , 1993, British journal of haematology.

[30]  B. Erman,et al.  Regulation of lymphoid-specific immunoglobulin mu heavy chain gene enhancer by ETS-domain proteins. , 1993, Science.

[31]  M. Klemsz,et al.  PU.1 recruits a second nuclear factor to a site important for immunoglobulin kappa 3' enhancer activity , 1992, Molecular and cellular biology.

[32]  H. Schöler,et al.  Octamania: the POU factors in murine development. , 1991, Trends in genetics : TIG.

[33]  M. Rosenfeld.  POU-domain transcription factors: pou-er-ful developmental regulators. , 1991, Genes & development.

[34]  M. Klemsz,et al.  The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene , 1990, Cell.

[35]  W. Schaffner,et al.  A cloned octamer transcription factor stimulates transcription from lymphoid–specific promoters in non–B cells , 1988, Nature.

[36]  G. Ruvkun,et al.  The POU domain: a large conserved region in the mammalian pit-1, oct-1, oct-2, and Caenorhabditis elegans unc-86 gene products. , 1988, Genes & development.

[37]  W. Schaffner,et al.  Cell type‐specificity elements of the immunoglobulin heavy chain gene enhancer. , 1987, The EMBO journal.

[38]  M. Neuberger,et al.  Transcription cell type specificity is conferred by an immunoglobulin VH gene promoter that includes a functional consensus sequence , 1985, Cell.

[39]  D. Baltimore,et al.  Two regulatory elements for immunoglobulin kappa light chain gene expression. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[40]  W. Murphy,et al.  Structure of the 5' ends of immunoglobulin genes: a novel conserved sequence. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[41]  H. Zachau,et al.  Correct transcription of an immunoglobulin κ gene requires an upstream fragment containing conserved sequence elements , 1984, Nature.

[42]  H Stein,et al.  Immunoenzymatic labeling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes). , 1984, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[43]  S. Tonegawa,et al.  A tissue-specific transcription enhancer element is located in the major intron of a rearranged immunoglobulin heavy chain gene , 1983, Cell.

[44]  S. Hsu,et al.  The use of antiavidin antibody and avidin-biotin-peroxidase complex in immunoperoxidase technics. , 1981, American journal of clinical pathology.

[45]  P. Gaulard,et al.  Primary mediastinal B-cell lymphoma: high frequency of BCL-6 mutations and consistent expression of the transcription factors OCT-2, BOB.1, and PU.1 in the absence of immunoglobulins. , 2003, The American journal of pathology.

[46]  A. Rolink,et al.  B cell development and immunoglobulin gene transcription in the absence of Oct-2 and OBF-1 , 2001, Nature Immunology.

[47]  L. Staudt,et al.  Immunoglobulin gene transcription. , 1991, Annual review of immunology.