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• W2031780590 abstract "Hodgkin’s disease (HD) is a lymphoproliferative disease of predominantly B-cell origin. However, the reasons for the incomplete development of the B-cell phenotype and lack of immunoglobulin expression in classical HD (cHD) have not been fully explained. We examined the expression of PU.1 in HD, an Ets-family transcription factor, which regulates the expression of immunoglobulin and other genes that are important for B-cell development. Immunohistochemistry for PU.1 was performed on 35 cases of cHD and 15 cases of lymphocyte predominance HD as well as 67 non-Hodgkin’s lymphomas (NHL). Expression of PU.1 was studied by Western blotting in four cHD-derived cell lines and in five NHL cell lines. We also studied the expression of two additional B-cell transcription factors, B-cell-specific activator protein and Oct-2. Our results show a striking lack of PU.1 expression by neoplastic cells in cHD but not in lymphocyte predominance HD. Our study also confirmed that B-cell-specific activator protein but not Oct-2 is not expressed by cHD. Western blotting showed no PU.1 protein expression in the cHD-derived cell lines, with the exception of one cell line of putative monocyte/histiocyte origin. The lack of PU.1 protein expression in cHD likely contributes to the lack of immunoglobulin expression and incomplete B-cell phenotype characteristic of the Reed-Sternberg cells in cHD. Hodgkin’s disease (HD) is a lymphoproliferative disease of predominantly B-cell origin. However, the reasons for the incomplete development of the B-cell phenotype and lack of immunoglobulin expression in classical HD (cHD) have not been fully explained. We examined the expression of PU.1 in HD, an Ets-family transcription factor, which regulates the expression of immunoglobulin and other genes that are important for B-cell development. Immunohistochemistry for PU.1 was performed on 35 cases of cHD and 15 cases of lymphocyte predominance HD as well as 67 non-Hodgkin’s lymphomas (NHL). Expression of PU.1 was studied by Western blotting in four cHD-derived cell lines and in five NHL cell lines. We also studied the expression of two additional B-cell transcription factors, B-cell-specific activator protein and Oct-2. Our results show a striking lack of PU.1 expression by neoplastic cells in cHD but not in lymphocyte predominance HD. Our study also confirmed that B-cell-specific activator protein but not Oct-2 is not expressed by cHD. Western blotting showed no PU.1 protein expression in the cHD-derived cell lines, with the exception of one cell line of putative monocyte/histiocyte origin. The lack of PU.1 protein expression in cHD likely contributes to the lack of immunoglobulin expression and incomplete B-cell phenotype characteristic of the Reed-Sternberg cells in cHD. PU.1 (PU.1) belongs to the Ets-family of transcription factors. It is expressed in the myeloid lineage and in immature as well as mature B lymphocytes with the exception of plasma cells. PU.1 is essential during early B-cell differentiation. The absence of PU.1 results in a total block of B-cell development at the pre-pro stage.1McKercher SR Torbett BE Anderson KL Henkel GW Vestal DJ Baribault H Klemsz M Feeney AJ Wu GE Paige CJ Maki RA Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities.EMBO J. 1996; 15: 5647-5658Crossref PubMed Scopus (934) Google Scholar Very little is known about PU.1 function in later stages of B-cell development. PU.1 does not seem to play a role in the end-stage of B-cell development and is not expressed in plasma cells. Accordingly, PU.1 DNA binding activity, PU.1 mRNA expression and PU.1-dependent transactivation were found to be absent or detectable only at a very low level in a number of multiple myeloma cell lines.2Pettersson M Sundstrom C Nilsson K Larsson LG The hematopoietic transcription factor PU.1 is downregulated in human multiple myeloma cell lines.Blood. 1995; 86: 2747-2753Crossref PubMed Google Scholar PU.1 exerts an important role in the regulation of the expression of crucial B-cell proteins such as immunoglobulin (Ig) genes, CD79, CD20, and CD72.3Oikawa T Yamada T Kihara-Negishi F Yamamoto H Kondoh N Hitomi Y Hashimoto Y The role of Ets family transcription factor PU.1 in hematopoietic cell differentiation, proliferation and apoptosis.Cell Death Differ. 1999; 6: 599-608Crossref PubMed Scopus (78) Google Scholar PU.1 binds to the 3′ enhancer region of both the Ig kappa and lambda light chain genes whereas it also regulates the immunoglobulin heavy chain genes through the intron enhancer region.4Pongubala JM Nagulapalli S Klemsz MJ McKercher SR Maki RA Atchison ML PU.1 recruits a second nuclear factor to a site important for immunoglobulin kappa 3′ enhancer activity.Mol Cell Biol. 1992; 12: 368-378Crossref PubMed Scopus (313) Google Scholar, 5Eisenbeis CF Singh H Storb U PU.1 is a component of a multiprotein complex which binds an essential site in the murine immunoglobulin lambda 2-4 enhancer.Mol Cell Biol. 1993; 13: 6452-6461Crossref PubMed Google Scholar, 6Nelsen B Tian G Erman B Gregoire J Maki R Graves B Sen R Regulation of lymphoid specific immunoglobulin mu heavy chain gene enhancer by ETS-domain proteins.Science. 1993; 261: 82-86Crossref PubMed Scopus (196) Google Scholar, 7Rivera RR Stuiver MH Steenbergen R Murre C Ets proteins: new factors that regulate immunoglobulin heavy-chain gene expression.Mol Cell Biol. 1993; 13: 7163-7169Crossref PubMed Scopus (83) Google Scholar In addition, several promotor regions of the immunoglobulin variable genes as well as J chain gene have also been shown to bind PU.1.8Shin MK Koshland ME Ets-related protein PU.1 regulates expression of the immunoglobulin J-chain gene through a novel Ets-binding element.Genes Dev. 1993; 7: 2006-2015Crossref PubMed Scopus (122) Google Scholar PU.1 exerts its function in a number of enhancer (eg, the Ig gene) or promotors (eg, the CD20 gene) in cooperation with a second transcription factor Pip.9Himmelmann A Riva A Wilson GL Lucas BP Thevenin C Kehrl JH PU.1/Pip and a basic helix loop helix zipper transcription factors interact with binding sites in the CD20 promoter to help confer lineage- and stage-specific expression of CD20 in B lymphocytes.Blood. 1997; 90: 3984-3995Crossref PubMed Google Scholar PU.1 has also been shown to act by cooperating with several other transcription factors such as c-jun and c-fos.10Eisenbeis CF Singh H Storb U Pip, a novel IRF family member, is a lymphoid-specific PU.1-dependent transcriptional activator.Genes Dev. 1995; 9: 1377-1387Crossref PubMed Scopus (417) Google Scholar, 11Pongubala JMR Atchison ML PU.1 can participate in an active enhancer complex without its transcriptional activation domain.Biochemistry. 1997; 94: 127-132Google Scholar In addition to a number of other genes such as major histocompatibility complex class II, interleukin (IL)-5 receptor α and PU.1 itself, PU.1 targets promoters/enhancers of at least 24 myelomonocyte/granulocyte genes (M-CSF receptor, G-CSF receptor, GM-CSF receptor, CD11b, CD11c, CD18, myeloperoxidase, and others), four megakaryocyte/erythrocyte genes (GPIIb, PBP, β-globin intervening sequence 2, and glutathione peroxidase), and three viral genes (EB virus EBNA2, SV40, and equine infectious anemia virus).3Oikawa T Yamada T Kihara-Negishi F Yamamoto H Kondoh N Hitomi Y Hashimoto Y The role of Ets family transcription factor PU.1 in hematopoietic cell differentiation, proliferation and apoptosis.Cell Death Differ. 1999; 6: 599-608Crossref PubMed Scopus (78) Google Scholar The role of the transcription factor PU.1 in hematopoiesis has been extensively reviewed elsewhere.12Tenen DG Hromas R Licht JD Zhang DE Transcription factors, normal myeloid development, and leukemia.Blood. 1997; 90: 489-519Crossref PubMed Google Scholar, 13McKercher SR Henkel GW Maki RA The transcription factor PU.1 does not regulate lineage commitment but has lineage-specific effects.J Leukoc Biol. 1999; 66: 727-732Crossref PubMed Scopus (27) Google Scholar, 14Simon MC PU.1 and hematopoiesis: lessons learned from gene targeting experiments.Semin Immunol. 1998; 10: 111-118Crossref PubMed Scopus (40) Google Scholar, 15Fisher RC Scott EW Role of PU.1 in hematopoiesis.Stem Cells. 1998; 16: 25-37Crossref PubMed Scopus (135) Google Scholar It has been recently shown that different levels of expression of PU.1 transcription factor determines cell fate in the hematopoietic system. A high level of expression promotes macrophage differentiation and blocks B-cell development whereas a low level of expression favors B-cell development.16DeKoter RP Singh H Regulation of B lymphocyte and macrophage development by graded expression of PU.1.Science. 2000; 288: 1439-1441Crossref PubMed Scopus (570) Google Scholar Interactions between PU.1 and GATA proteins play a critical role in the decision of stem cells to commit to erythroid versus myeloid lineage.17Zhang P Behre G Pan J Iwama A Wara-Aswapati N Radomska HS Auron PE Tenen DG Sun Z Negative cross-talk between hematopoietic regulators: GATA proteins repress PU.1.Proc Natl Acad Sci USA. 1999; 96: 8705-8710Crossref PubMed Scopus (376) Google Scholar PU.1 also plays a role in dendritic cell development and is required for myeloid-derived but not lymphoid-derived dendritic cells.18Guerriero A Langumuir PB Spain LM Scott EW PU.1 is required for myeloid-derived but not lymphoid-derived dendritic cells.Blood. 2000; 95: 879-885Crossref PubMed Google Scholar Oct-2 is an additional important transcription factor in B cells that targets the immunoglobulin promotors. However, it is not necessary for the maintenance of Ig gene expression in a differentiated B cell.19Feldhaus AL Klug CA Arvin KL Singh H Targeted disruption of the Oct-2 locus in a B-cell provides genetic evidence for two distinct cell-type specific pathways of octamer element-mediated gene activation.EMBO J. 1993; 12: 2763-2772Crossref PubMed Scopus (70) Google Scholar The study of Oct-2−/− mice has shown that the Oct-2 gene is essential for survival, but normal numbers of surface Ig-positive B cells develop in the fetal liver. Thus, Oct-2 seems not to be essential for B-cell development nor for regulating the expression of the Ig genes. However, Oct-2 does seem to play a role in germinal center cell formation and further differentiation of B cells into IgG-producing cells and plasma cells and therefore is important for the maintenance of the mature B-cell pool.20Corcorean LM Karvelas M Nossal GJV Ye Z-S Jacks T Baltimore D Oct-2, although not required for early B-cell development, is critical for later B-cell maturation and for postnatal survival.Genes Dev. 1993; 7: 570-582Crossref PubMed Scopus (240) Google Scholar, 21Schubart K Massa S Schubart D Corcoran LM Rolink AG Matthias P B cell development and immunoglobulin gene transcription in the absence of Oct-2 and OBF-1.Nature Immunol. 2001; 2: 69-74Crossref PubMed Scopus (99) Google Scholar HD has been demonstrated to predominantly represent a clonal disease of B-cell origin by virtue of the frequent rearrangement of immunoglobulin genes by Reed-Sternberg cells (RS), the neoplastic cells of HD.22Küppers R Rajewsky K Zhao M Simons G Laumann R Fischer R Hansmann ML Hodgkin's disease: Hodgkin and Reed-Sternberg cells picked from histological sections show clonal immunoglobulin gene rearrangements and appear to be derived from B-cells at various stages of development.Proc Natl Acad Sci USA. 1994; 91: 10962-10966Crossref PubMed Scopus (553) Google Scholar, 23Tamaru J Hummel M Zemlin M Kalvelage B Stein H Hodgkin's disease with a B-cell phenotype often shows a VDJ rearrangements and somatic mutations in the VH genes.Blood. 1994; 84: 708-715PubMed Google Scholar, 24Ohno T Stribley JA Wu G Hinrichs SH Weisenburger DD Chan WC Clonality in nodular lymphocyte-predominant Hodgkin's disease.N Engl J Med. 1997; 337: 459-465Crossref PubMed Scopus (130) Google Scholar, 25Marafioti T Hummel M Anagnostopoulos I Foss HD Falini B Delsol G Isaacson PG Pileri S Stein H Origin of nodular lymphocyte-predominant Hodgkin's disease from a clonal expansion of highly mutated germinal-center B-cells.N Engl J Med. 1997; 337: 453-458Crossref PubMed Scopus (272) Google Scholar, 26Braeuninger A Küppers R Strickler JG Wacker HH Rajewsky K Hansman ML Hodgkin and Reed-Sternberg cells in lymphocyte predominant Hodgkin's disease represent clonal populations of germinal center-derived tumor B-cells.Proc Natl Acad Sci USA. 1997; 94: 9337-9342Crossref PubMed Scopus (233) Google Scholar Interestingly, Reed-Sternberg cells mostly show a partial B-cell phenotype. Indeed, the Reed-Sternberg cells of classical Hodgkin’s disease (cHD) infrequently express B-cell surface antigens or immunoglobulins in contrast with the neoplastic cells of most non-Hodgkin’s B-cell lymphomas (B-NHL) and lymphocytic predominance Hodgkin’s disease (LPHD).27Mason DY Banks PM Chan J Cleary ML Delsol G de Wolf Peeters C Falini B Gatter K Grogan TM Harris NL Isaacson PG Jaffe ES Knowles DM Müller-Hermelink HK Pileri S Ralfkiaer E Stein H Warnke R Nodular lymphocyte predominance Hodgkin's disease. A clinicopathological entity.Am J Surg Pathol. 1994; 18: 526-530Crossref PubMed Scopus (167) Google Scholar, 28Schmid C Pan L Diss T Isaacson PG Expression of B-cell antigens by Hodgkin's and Reed-Sternberg cells.Am J Pathol. 1991; 139: 701-707PubMed Google Scholar, 29Carbone A Gloghini A Gaidano G Franceschi S Capello D Drexler HG Falini B Dalla-Favera R Expression status of BCL-6 and syndecan-1 identifies distinct histogenetic subtypes of Hodgkin's disease.Blood. 1998; 92: 2220-2228PubMed Google Scholar, 30Watanabe K Yamashita Y Nakayama A Hasegawa Y Kojima H Nagasawa T Mori N Varied B-cell immunophenotypes of Hodgkin/Reed-Sternberg cells in classic Hodgkin's disease.Histopathology. 2000; 36: 353-361Crossref PubMed Scopus (67) Google Scholar Because normal B-cell development is not possible without the transcription factor PU.1 and the B-lymphocyte phenotype is tightly regulated by PU.1, we wanted to investigate in the present study whether the HD phenotype might be related to aberrant PU.1 protein expression. A total of 125 cases were collected from the files of the Department of Pathology, The Norwegian Radium Hospital. Included were the following diagnoses: cHD (35 cases), lymphocyte predominance Hodgkin’s lymphoma (LPHD, 15 cases), various B-cell non-Hodgkin’s lymphomas (B-NHL, 43 cases) and T-cell non-Hodgkin’s lymphomas (T-NHL, 24 cases). Eight reactive lymph nodes were also studied. Included were lymph nodes showing follicular hyperplasia (four cases), dermatopathic lymphadenopathy (one case), sinus histiocytosis (one case), and sarcoidosis (two cases). Formalin-fixed or B5-fixed paraffin-embedded tissues were available for all cases. The following cell-lines were used: three HD-derived cell lines (KM-H2, L-428, HDLM-2), one putative HD cell line with histiocytic differentiation (HD-MY-Z), two human anaplastic large-cell lymphoma cell lines (SR-786 and SU-DHL-1), one Burkitt’s lymphoma cell line (Namalwa), one T-lymphoblastic leukemia cell line (Jurkat), and one follicular lymphoma cell line (ROS-50).31Kamesaki H Fukuhara S Tatsumi E Uchino H Yamabe H Miwa H Shirakawa S Hatanaka M Honjo T Cytochemical, immunologic, chromosomal, and molecular genetic analysis of a novel cell line derived from Hodgkin's disease.Blood. 1986; 68: 285-292Crossref PubMed Google Scholar, 32Schaadt M Fonatsch C Kirchner H Diehl V Establishment of a malignant, Epstein-Barr-virus (EBV)-negative cell-line from the pleura effusion of a patient with Hodgkin's disease.Blut. 1979; 38: 185-190Crossref PubMed Scopus (62) Google Scholar, 33Drexler HG Gaedicke G Lok MS Diehl V Minowada J Hodgkin's disease derived cell lines HDLM-2 and L-428: comparison of morphology, immunological and isoenzyme profiles.Leuk Res. 1986; 10: 487-500Abstract Full Text PDF PubMed Scopus (91) Google Scholar, 34Epstein AL Kaplan HS Biology of the human malignant lymphomas. I. Establishment in continuous cell culture and heterotransplantation of diffuse histiocytic lymphomas.Cancer. 1974; 34: 1851-1872Crossref PubMed Scopus (96) Google Scholar, 35Nadkarni JS Nadkarni JJ Clifford P Manolov G Fenyo EM Klein E Characteristics of new cell lines derived from Burkitt lymphomas.Cancer. 1969; 23: 64-79Crossref PubMed Scopus (114) Google Scholar, 36Schneider U Schwenk HU Bornkamm G Characterization of EBV-genome negative “null” and “T” cell lines derived from children with acute lymphoblastic leukemia and leukemic transformed non-Hodgkin lymphoma.Int J Cancer. 1977; 19: 521-526Crossref Scopus (543) Google Scholar, 37Bargou RC Mapara MY Zugck C Daniel PT Pawlita M Dohner H Dorken B Characterization of a novel Hodgkin cell line, HD-MyZ, with myelomonocytic features mimicking Hodgkin's disease in severe combined immunodeficient mice.J Exp Med. 1993; 177: 1257-1268Crossref PubMed Scopus (51) Google Scholar, 38Beckwith M Longo DL O'Connell CD Moratz CM Urba WJ Phorbol ester-induced, cell-cycle-specific, growth inhibition of human B-lymphoma cell lines.J Natl Cancer Inst. 1990; 82: 501-509Crossref PubMed Scopus (71) Google Scholar, 39van Ooteghem RB Smit EM Beishuizen A Lambrechts AC vd Blij-Philipsen M Smilde TJ Hagemeijer A A new B-cell line showing a complex translocation (8;14;18) and BCL2 rearrangement.Cancer Genet Cytogenet. 1994; 74: 87-94Abstract Full Text PDF PubMed Scopus (25) Google Scholar All cell lines were obtained from DSMZ (Braunschweig, Germany) with the exception of ROS-50 that was a kind gift from Dr. R. Slater, University Hospitals of Rotterdam, The Netherlands. The monoclonal anti-human PU.1 antibody (clone G148-74) was purchased from Pharmingen (San Diego, CA), mouse anti-B-cell-specific activator protein (BSAP) (anti-Pax-5, clone 24) from Transduction Laboratories (Lexington, KY), and Oct-2 (AB-1) from Oncogene Research Products (Boston, MA). The monoclonal PU.1, BSAP, and Oct-2 antibodies were used for immunohistochemistry and immunocytochemistry. The polyclonal anti-PU.1 antibody was purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA) and used for Western blot analysis and immunocytochemistry. Formalin-fixed and paraffin-embedded or B5-fixed and paraffin-embedded tissues were cut at 4 μm. The sections were pretreated in a microwave oven (Electrolux microwave, 850 W) by cooking in ethylenediaminetetraacetic acid antigen retrieval solution at pH 8. Subsequently, the sections were incubated with the primary antibody (dilution, 1:10) for 30 minutes and stained using the EnVison kit (DAKO, Glostrup, Denmark). Cytospins prepared from cell cultures were air-dried and stored frozen until use. Before use, cytospins were fixed in acetone for 2 minutes, air-dried again, incubated with primary antibody (dilution, 1:10) for 30 minutes and stained by the EnVision method. Formalin-fixed tissue was available for all of the cases. B5-fixed tissue was available in 40% of the cases and was studied in parallel with formalin-fixed tissue to evaluate differences because of different tissue fixation. The staining pattern was designated as “diffuse” if the staining was found in all malignant cells and as “focal” if present only in a fraction of malignant cells. Cells (106) were lysed in Laemmli buffer and heated at 95°C for 5 minutes and subsequently loaded onto the gel. Alternatively, 25 μg of protein as measured by the Bradford assay were used. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis using 10% polyacrylamide gels and transfer of proteins to nitrocellulose filters were performed as described previously.40Laemmli UK Cleavage of structural proteins during the assembly of the head of bacteriophage T4.Nature. 1970; 277: 680-685Crossref Scopus (207538) Google Scholar, 41Towbin H Staehelin T Gordon J Electrophoretic transfer of proteins from gels to nitrocellulose sheets: procedure and some applications.Proc Natl Acad Sci USA. 1979; 76: 4350-4354Crossref PubMed Scopus (44939) Google Scholar The transfer of proteins as well as amount of proteins was checked with Ponceaus S solution. After inactivation with 5% milk solution in phosphate-buffered saline with 1% Tween 20, the blots were incubated for 2 hours with the anti-PU.1 polyclonal antibody at a final concentration of 1 μg/ml. After washing, the blots were incubated for 45 minutes with peroxidase-labeled swine anti-rabbit IgG at a final concentration of 0.2 μg/ml. Subsequently, the blots were washed again and incubated with enhanced chemiluminescence detection reagents (Amersham, Buckinghamshire, England) after which they were exposed to autoradiographic film first for 2 minutes, and subsequently for 15 minutes. The results were very uniform and reproducible with the anti-human PU.1, anti-Pax-5, and anti-Oct-2 antibodies. The anti-human PU.1 antibody labeled lymphocytes in B-cell compartments of the lymph node and histiocytes. Lymphocytes in B-cell compartments, but no other cells of the lymph node showed strong and uniform nuclear positivity with anti-Pax-5. The intensity of staining with anti-human PU.1 varied in various cell types. The staining intensity was the strongest in histiocytes, moderate and uniform in mantle B cells, whereas the majority of germinal center B cells showed a moderate intensity of staining. No expression of either PU.1 or BSAP was detected in plasma cells. Plasmacytoid monocytes expressed PU.1, but not BSAP. Oct-2 was variably expressed in germinal center cells, weak or negative in mantle zone, and weak to moderate in plasma cells. A subpopulation of germinal center cells showed the strongest expression. No expression of Oct-2 was found in any other cell type. cHD was classified as follows: nodular sclerosis (20 cases), mixed cellularity (9 cases), lymphocyte depletion (3 cases), and lymphocyte-rich (3 cases). There were 15 cases of LPHD. The immunophenotypes of the neoplastic cells in cHD are summarized as follows: 100% CD30, 70% CD15, 28% CD20 (occasional cells with variable intensity), 23% CD45 (occasional cells), and 7% CD3 (rare cells). The expression of the CD20, CD45, and CD3 was only seen in a small subpopulation of Hodgkin’s cells in these respective cases. The neoplastic cells in all cases of LPHD expressed CD45 and CD20 (diffuse expression, variable intensity), but no positivity was found for either CD30 or CD15. The results of immunohistological evaluation of PU.1, BSAP, and Oct-2 protein expression are summarized in Table 1, Table 2. Figure 1, Figure 2 show the results of immunohistochemical study of PU.1 and BSAP expression. A striking difference in the expression of the PU.1 protein was found between cHD and LPHD (Figure 1). In all cases of LPHD, the neoplastic cells (popcorn cells, L&H cells) showed nuclear positivity for PU.1, whereas only in 1 of the 35 cases of cHD neoplastic cells unequivocally expressed PU.1. In all cases of cHD included in the study, histiocytes as well as small B lymphocytes were invariably positive such as observed in the reactive lymph nodes. Variable cytoplasmic positivity in malignant cells was noted in 62% of cHD and 34% of LPHD cases.Table 1PU.1, BSAP, and Oct-2 Expression in Hodgkin's LymphomaDiagnosisPU.1 (%)BSAP (%)Oct-2 (%)Classical HD2/35 (5.7)27/29 (93)0/29 (0)LPHD15/15 (100)15/15 (100)15/15 (0) Open table in a new tab Table 2PU.1, BSAP, and Oct-2 Expression in Non-Hodgkin's LymphomaDiagnosisPU.1 (%)BSAP (%)Oct-2 (%)B-NHL29/43 (67)21/22 (95)32/36 (89) CLL/SLL*Including one case of lymphoplasmacytic lymphoma.6/6 (100)2/2 (100)3/3 (100) FL7/7 (100)2/2 (100)4/4 (100) MCL2/3 (67)2/2 (100)4/6 (67) MZL3/3 (100)2/2 (100)2/2 (100) DLBCL†Excluding TCRBCL.11/18 (61)9/10 (90)15/17 (88) TCRBCL0/6 (0)4/4 (100)4/4 (100)PTCL0/17 (0)0/17 (0)ALCL0/7 (0)0/7 (0)B-NHL, B-cell non-Hodgkin's lymphoma; CLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; MZL, extranodal marginal zone lymphoma of MALT type; DLBCL, diffuse large B-cell lymphoma; TCRBCL, T-cell-rich B-cell lymphoma; PTCL, peripheral T-cell lymphoma; ALCL, anaplastic large cell lymphoma.* Including one case of lymphoplasmacytic lymphoma.† Excluding TCRBCL. Open table in a new tab Figure 2BSAP is expressed in all subtypes of HD and B-NHL. Immunohistochemical analysis on paraffin-embedded tissues using monoclonal anti-Pax-5 antibody (immunostaining by the EnVision method using diaminobenzidine as a chromogen).A, B, and C: Reed-Sternberg cells in nodular sclerosis cHD, mixed cellularity cHD, and neoplastic cells of LPHD, respectively, show nuclear BSAP expression. The level of BSAP expression by neoplastic cells varies from case to case as illustrated by the low level of expression of the case shown in A. Small B lymphocytes, but not T lymphocytes or histocytes in the background also express the protein. D: BSAP is expressed in neoplastic cells of DLBCL.View Large Image Figure ViewerDownload Hi-res image Download (PPT) B-NHL, B-cell non-Hodgkin's lymphoma; CLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; MZL, extranodal marginal zone lymphoma of MALT type; DLBCL, diffuse large B-cell lymphoma; TCRBCL, T-cell-rich B-cell lymphoma; PTCL, peripheral T-cell lymphoma; ALCL, anaplastic large cell lymphoma. In all cases of LPHD and all, but two cases of cHD, neoplastic cells were positive for BSAP (Figure 2). The intensity of the staining varied from weak to strong in the neoplastic cells, whereas it was invariably strong in the small benign B lymphocytes. Oct-2 was not expressed in any of the cases of cHD in our study. Also, all cases of LPHD expressed Oct-2. The results are shown in Table 2. B-NHLs were positive for BSAP except for a single case of plasmablastic lymphoma that was negative. Interestingly, 33% of B-NHL were negative for PU.1 (Figure 1) and 11% for Oct-2. Double-negative phenotype, PU.1−/Oct-2−, was found characteristically in all but two cases of cHD. In contrast to cHD, all cases of LPHD were positive for PU.1 and Oct-2. Also, 1 of 17 cases of diffuse large B-cell lymphoma (DLBCL) (5.8%) was double-negative for PU.1 and Oct-2. Forty-seven percent of DLBCL had double-positive phenotype such as LPHD. The results of PU.1 expression by the cell lines are shown in Table 3. The HD-MYZ cell line showed cytoplasmic positivity with polyclonal PU.1 antibody. However, monoclonal PU.1 antibody detected very weak nuclear expression in an occasional cell. The L428, HDLM-2, and KM-H2 HD-derived cell lines were negative using both polyclonal and monoclonal PU.1 antibody. The Namalwa cell line showed occasional cells with weak, but definite positivity. The Jurkat cell line was negative with both antibodies. The SU-DHL-1 anaplastic large-cell lymphoma cell line showed borderline cytoplasmic and nuclear positivity with monoclonal, but not polyclonal PU.1 antibody. However, SR-786, another anaplastic large-cell lymphoma cell line was found to be negative with both PU.1 antibodies. The control cell line ROS.50 showed strong nuclear positivity with both monoclonal and polyclonal anti-PU.1 antibody.Table 3Immunocytochemical Detection of PU.1 in Hodgkin's and Non-Hodgkin's Lymphoma-Derived Cell LinesCell lineMonoclonal PU.1Polyclonal PU.1HD-MY-Z+/−−HDLM-2−−L-428−−KM-H2−−Namalwa++Jurkat−−SU-DHL-1−/+−SR-786−−ROS-50++++++, strong; +, weak; +/−, very weak; −/+, borderline. Open table in a new tab ++, strong; +, weak; +/−, very weak; −/+, borderline. The results are illustrated in Figure 3. The ROS-50 follicular lymphoma cell line showed the strongest band of the appropriate molecular weight (∼42 kd) that was also present in the peripheral blood mononuclear cell sample. An identical, but much weaker band was detected after prolonged exposure of the radiographic film in the Namalwa cell line. Three of the HD-derived cell lines did not reveal PU.1 expression. The HD-MYZ, a putative HD-derived cell line with monocytic differentiation displayed an anti-PU.1 reactive protein migrating at ∼50 kd. The Jurkat and the two anaplastic large cell lymphoma (ALCL) cell lines were negative for PU.1 expression. Our study shows a striking absence of PU.1 expression by Hodgkin cells in cHD as compared to LPHD. In addition, normal PU.1 protein was not found to be expressed by three cHD-derived cell lines and the HD-MY-Z, a putative HD cell line. PU.1 is a transcription factor necessary for B-cell development and regulates a diversity of genes important for B-cell differentiation. Among the genes regulated by PU.1 are the Ig genes including heavy chain, J-chain, and both light chain genes, as well as the CD20 gene and the mb-1 gene.4Pongubala JM Nagulapalli S Klemsz MJ McKercher SR Maki RA Atchison ML PU.1 recruits a second nuclear factor to a site important for immunoglobulin kappa 3′ enhancer activity.Mol Cell Biol. 1992; 12: 368-378Crossref PubMed Scopus (313) Google Scholar, 5Eisenbeis CF Singh H Storb U PU.1 is a component of a multiprotein complex which binds an essential site in the murine immunoglobulin lambda 2-4 enhancer.Mol Cell Biol. 1993; 13: 6452-6461Crossref PubMed Google Scholar, 6Nelsen B Tian G Erman B Gregoire J Maki R Graves B Sen R Regulation of lymphoid specific immunoglobulin mu heavy chain gene enhancer by ETS-domain proteins.Science. 1993; 261: 82-86Crossref PubMed Scopus (196) Google Scholar, 7Rivera RR Stuiver MH Steenbergen R Murre C Ets proteins: new factors that regulate immunoglobulin heavy-chain gene expression.Mol Cell Biol. 1993; 13: 7163-7169Crossref PubMed Scopus (83) Google Scholar, 8Shin MK Koshland ME Ets-related protein PU.1 regulates expression" @default.
• W2031780590 created "2016-06-24" @default.
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• W2031780590 creator A5023623204 @default.
• W2031780590 creator A5074819403 @default.
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• W2031780590 date "2001-11-01" @default.
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• W2031780590 title "The Transcription Factor PU.1, Necessary for B-Cell Development Is Expressed in Lymphocyte Predominance, But Not Classical Hodgkin’s Disease" @default.
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