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• W2080411938 abstract "SHP-1 is an important negative regulator of signaling by several receptors including receptors for interleukin-2 (IL-2R) and other cytokines. SHP-1 acts by dephosphorylating the receptors and receptor-associated kinases such as IL-2R-associated Jak3 kinase. We found that SHP-1 protein was not detectable or greatly diminished in most (six of seven) T cell lines derived from various types of T cell lymphomas and all (eight of eight) cutaneous T-cell lymphoma tissues with a transformed, large-cell morphology. All T-cell lymphoma lines tested (eight of eight) expressed diminished amounts or no detectable SHP-1 mRNA. These T cell lines did not, however, carry any mutations in the SHP-1 gene-coding, splice-junction, and promoter regions. Importantly, SHP-1 DNA promoter region in the T cell lines was resistant to digestion with three different methylation-sensitive restriction enzymes. This resistance was reversed by treatment of the cells with a demethylating agent, 5-deoxyazacytidine. The treatment resulted also in the expression of SHP-1 mRNA and, less frequently, SHP-1 protein. The expression of SHP-1 protein was associated with dephosphorylation of the Jak3 kinase. These results show that lack of SHP-1 expression is frequent in malignant T cells and results from methylation of the SHP-1 gene promoter. Furthermore, they indicate that SHP-1 loss may play a role in the pathogenesis of T cell lymphomas by permitting persistence of signals generated by IL-2R and, possibly, other receptor complexes. SHP-1 is an important negative regulator of signaling by several receptors including receptors for interleukin-2 (IL-2R) and other cytokines. SHP-1 acts by dephosphorylating the receptors and receptor-associated kinases such as IL-2R-associated Jak3 kinase. We found that SHP-1 protein was not detectable or greatly diminished in most (six of seven) T cell lines derived from various types of T cell lymphomas and all (eight of eight) cutaneous T-cell lymphoma tissues with a transformed, large-cell morphology. All T-cell lymphoma lines tested (eight of eight) expressed diminished amounts or no detectable SHP-1 mRNA. These T cell lines did not, however, carry any mutations in the SHP-1 gene-coding, splice-junction, and promoter regions. Importantly, SHP-1 DNA promoter region in the T cell lines was resistant to digestion with three different methylation-sensitive restriction enzymes. This resistance was reversed by treatment of the cells with a demethylating agent, 5-deoxyazacytidine. The treatment resulted also in the expression of SHP-1 mRNA and, less frequently, SHP-1 protein. The expression of SHP-1 protein was associated with dephosphorylation of the Jak3 kinase. These results show that lack of SHP-1 expression is frequent in malignant T cells and results from methylation of the SHP-1 gene promoter. Furthermore, they indicate that SHP-1 loss may play a role in the pathogenesis of T cell lymphomas by permitting persistence of signals generated by IL-2R and, possibly, other receptor complexes. SHP-1 is a member of the nontransmembrane phosphotyrosine phosphatases expressed predominantly in cells of the hematopoietic lineage.1Plutzky J Neel BG Rosenberg RD Isolation of a src homology 2-containing tyrosine phosphatase.Proc Natl Acad Sci USA. 1992; 89: 1123-1127Crossref PubMed Scopus (286) Google Scholar, 2Shen S-H Bastien L Posner BI Chre′tien P A protein-tyrosine phosphatase with sequence similarity to the SH2 domain of the protein-tyrosine kinases.Nature. 1991; 352: 736-739Crossref PubMed Scopus (336) Google Scholar, 3Yi T Cleveland JL Ihle JN Protein tyrosine phosphatase containing SH2 domains: characterization, preferential expression in hematopoietic cells, and localization to human chromosome 12p12–p13.Mol Cell Biol. 1992; 12: 836-846Crossref PubMed Scopus (306) Google Scholar, 4Matthews RJ Bowne DB Flores E Thomas ML Characterization of hematopoietic intracellular protein tyrosine phosphatases: description of a phosphatase containing an SH2 domain and another enriched in proline-, glutamic acid-, serine-, and threonine-rich sequences.Mol Cell Biol. 1992; 12: 2396-2405Crossref PubMed Scopus (325) Google Scholar, 5Ulyanova T Blasioli J Thomas ML Regulation of cell signaling by the protein tyrosine phosphatases, CD-45 and SHP-1.Immunol Res. 1997; 16: 101-113Crossref PubMed Scopus (24) Google Scholar SHP-1 is an important negative regulator involved in signaling through receptors for cytokine/growth factors such as c-kit ligand, CSF-1, erythropoietin, interleukin (IL)-3, IL-2, IL-4, and IL-13.6Klingmuller U Lorenz U Cantley LC Neel BG Lodish HF Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of Jak2 and termination of proliferative signals.Cell. 1995; 80: 729-738Abstract Full Text PDF PubMed Scopus (836) Google Scholar, 7Migone TS Calacano NA Migone TS Cacalano NA Taylor N Yi T Waldmann TA Johnston JA Recruitment of SH2-containing protein tyrosine phosphatase SHP-1 to the interleukin 2 receptor; loss of SHP-1 expression in human T-lymphotropic virus type I-transformed T cells.Proc Natl Acad Sci USA. 1998; 95: 3845-3850Crossref PubMed Scopus (112) Google Scholar, 8Haque SJ Harbor P Tabrizi M Yi T Williams BR Protein-tyrosine phosphatase Shp-1 is a negative regulator of IL-4- and IL-13-dependent signal transduction.J Biol Chem. 1998; 273: 33893-33896Crossref PubMed Scopus (148) Google Scholar A variety of noncytokine receptors including B-antigen receptor, T-antigen receptor, CD22, CD72,9Yeung Y-G Berg KL Pixley FJ Angeletti RH Stanley ER Protein tyrosine phosphatase-1C is rapidly phosphorylated in tyrosine in macrophages in response to colony stimulating factor-1.J Biol Chem. 1992; 267: 23447-23450Abstract Full Text PDF PubMed Google Scholar, 10Yi T Ihle JN Association of hematopoietic cell phosphatase with c-Kit after stimulation with c-Kit ligand.Mol Cell Biol. 1993; 13: 3350-3358Crossref PubMed Scopus (234) Google Scholar, 11Shultz LD Schweitzer PA Rajan TV Yi T Ihle JN Matthews RJ Thomas ML Beier DR Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene.Cell. 1993; 73: 1445-1454Abstract Full Text PDF PubMed Scopus (531) Google Scholar, 12Tsui HW Siminovitch KA de Souza L Tsui FW Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene.Nat Genet. 1993; 4: 124-129Crossref PubMed Scopus (512) Google Scholar, 13Wu Y Nadler MJ Brennan LA Gish GD Timms JF Fusaki N Jongstra-Bilen J Tada N Pawson T Wither J Neel BG Hozumi N The B-cell transmembrane protein CD72 binds to and is an in vivo substrate of the protein tyrosine phosphatase SHP-1.Curr Biol. 1998; 10: 1009-1017Abstract Full Text Full Text PDF Scopus (108) Google Scholar as well as the growing family of the inhibitory receptors expressed by natural killer and other types of cells also interact with SHP-1.14Long EO Regulation of immune responses through inhibitory receptors.Annu Rev Immunol. 1999; 17: 875-904Crossref PubMed Scopus (830) Google Scholar Association of SHP-1 with the majority of these receptors is mediated by phosphorylated tyrosine-based motifs.15Burshtyn DN Yang W Yi T Long EO A novel phosphotyrosine motif with a critical amino acid at position-2 for the SH2 domain-mediated activation of the tyrosine phosphatase SHP-1.J Biol Chem. 1997; 272: 13066-13072Crossref PubMed Scopus (161) Google Scholar, 16Burshtyn DN Lam AS Weston M Gupta N Warmerdam PA Long EO Conserved residues amino-terminal of cytoplasmic tyrosines contribute to the SHP-1-mediated inhibitory function of killer cell Ig-like receptors.J Immunol. 1999; 162: 897-902PubMed Google Scholar SHP-1 acts by dephosphorylating the receptors and receptor-associated tyrosine kinases.6Klingmuller U Lorenz U Cantley LC Neel BG Lodish HF Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of Jak2 and termination of proliferative signals.Cell. 1995; 80: 729-738Abstract Full Text PDF PubMed Scopus (836) Google Scholar, 17Shultz LD Schweitzer PA Rajan TV Yi T Ihle JN Matthews RJ Thomas ML Beier DR Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene.Cell. 1993; 73: 1445-1454Abstract Full Text PDF PubMed Scopus (685) Google Scholar Dysfunction of SHP-1 as seen in the natural SHP-1 gene knock-out, motheaten mice, results in hyperplasia of the erythroid and lymphoid lineages.18Shultz LD Rajan TV Greiner DL Severe defects in immunity and hematopoiesis caused by SHP-1 protein-tyrosine-phosphatase deficiency.Trends Biotech. 1997; 15: 302-307Abstract Full Text PDF PubMed Scopus (145) Google Scholar Signaling through the IL-2R receptor complex is vital for proper function of normal T lymphocytes. High-affinity IL-2R receptors are composed of α, β, and γc chains. γc is shared by the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15.19Leonard WJ O'Shea JJ JAKS AND STATS: biological implications.Annu Rev Immunol. 1998; 16: 293-322Crossref PubMed Scopus (1452) Google Scholar Inactivating mutations of γc result in severe combined immunodeficiency in humans and mice.20Noguchi M Yi H Rosenblatt HM Filipovich AH Adelstein S Modi WS McBride OW Leonard WJ Interleukin-2 receptor γ chain mutations result in X-linked severe combined immunodeficiency in humans.Cell. 1993; 73: 147-157Abstract Full Text PDF PubMed Scopus (1147) Google Scholar, 21Ohbo K Suda T Hashiyama M Mantani A Ikebe M Moriyama M Nakamura M Katsuki M Takahashi K Yamamura K Sugamura K Modulation of hematopoiesis in mice with a truncated mutant of the interleukin-2 receptor γ chain.Blood. 1996; 87: 956-967Crossref PubMed Google Scholar, 22DiSanto JP Muller W Guy-Grand D Fischer A Rajewsky K Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor γ chain.Proc Natl Acad Sci USA. 1995; 92: 377-381Crossref PubMed Scopus (747) Google Scholar, 23Cao X Shores EW Hu-Li J Anver MR Kelsall BL Russell SM Drago J Noguchi M Grinberg A Bloom ET Paul WE Katz SI Love PI Leonard WJ Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain.Immunity. 1995; 2: 223-238Abstract Full Text PDF PubMed Scopus (845) Google Scholar Interaction of IL-2 with IL-2R rapidly induces tyrosine phosphorylation of the IL-2R complex mediated by the receptor-associated Jak1 and Jak3 tyrosine kinases.24Johnston JA Kawamura M Kirken RA Chen YQ Blake TB Shibuya K Ortaldo JR McVicar DW O'Shea JJ Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2.Nature. 1994; 370: 151-153Crossref PubMed Scopus (501) Google Scholar, 25Russell SM Johnston JA Noguchi M Kawamura M Bacon CM Friedmann M Berg M McVicar DW Witthun BA Silvennoinen OAS Goldman AS Schmaisteg FC Ihle JN O'Shea JJ Leonard WJ Interaction of IL-1R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID.Science. 1994; 266: 1042-1045Crossref PubMed Scopus (582) Google Scholar, 26Beadling C Guschin D Witthuhn BA Ziemiecki A Ihle JN Kerr IM Cantrell DA Activation of JAK kinases and STAT proteins by interleukin-2 and interferon alpha, but not the T cell antigen receptor, in human T lymphocytes.EMBO J. 1994; 13: 5605-5615Crossref PubMed Scopus (192) Google Scholar This leads to phosphorylation of STAT3 and STAT5 molecules which translocate to the cell nucleus and activate transcription of the IL-2 responsive proteins.26Beadling C Guschin D Witthuhn BA Ziemiecki A Ihle JN Kerr IM Cantrell DA Activation of JAK kinases and STAT proteins by interleukin-2 and interferon alpha, but not the T cell antigen receptor, in human T lymphocytes.EMBO J. 1994; 13: 5605-5615Crossref PubMed Scopus (192) Google Scholar, 27Fujii H Nakagawa Y Schindler U Kawahara A Mori H Gouilleux F Groner B Ihle JN Minami Y Miyazaki T Taniguchi T Activation of Stat5 by interleukin 2 requires a carboxyl-terminal region of the interleukin 2 receptor beta chain but is not essential for the proliferative signal transmission.Proc Natl Acad Sci USA. 1995; 92: 5482-5486Crossref PubMed Scopus (193) Google Scholar, 28Nielsen M Svejgaard A Skov S Odum N Interleukin-2 induces tyrosine phosphorylation and nuclear translocation of STAT3 in human T lymphocytes.Eur J Immunol. 1994; 24: 3082-3086Crossref PubMed Scopus (66) Google Scholar Activation of Jak3 is critical for transduction of signals mediated by IL-2R complex because mutations of Jak3 result in severe combined immunodeficiency in both humans29Macchi P Villa A Gillani S Sacco MG Frattini A Porta F Ugazio AG Johnston JA Candotti F O'Shea JJ Vezzoni P Notarangelo LD Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID).Nature. 1995; 377: 65-68Crossref PubMed Scopus (726) Google Scholar, 30Russell SM Tayebi N Nakajima H Riedy MC Roberts JL Aman MJ Migone TS Noguchi M Markert ML Buckley RH O'Shea JJ Leonard WJ Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development.Science. 1995; 270: 797-800Crossref PubMed Scopus (668) Google Scholar and mice31Thomis DC Gurniak CB Tivol E Sharpe AH Berg LJ Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3.Science. 1995; 270: 794-797Crossref PubMed Scopus (470) Google Scholar, 32Nosaka T van Deursen JM Tripp RA Thierfelder WE Witthuhn BA McMickle AP Dohrty PC Grosveld GC Ihle JN Defective lymphoid development in mice lacking Jak3.Science. 1995; 270: 800-802Crossref PubMed Scopus (568) Google Scholar similar to the immunodeficiency seen in mutations of the γc chain. Previous studies have established that a number of human T cell leukemia virus type I (HTLV-I)-positive and -negative T cell lines exhibit constitutive activation of the IL-2R Jak/STAT signaling pathway33Migone TS Lin JX Cereseto A Mulloy JC O'Shea JJ Franchini G Leonard WJ Constitutively activated Jak-STAT pathway in T cells transformed with HTLV-I.Science. 1995; 269: 79-81Crossref PubMed Scopus (506) Google Scholar, 34Xu X Kang S-H Heidenreich O Okerholm M O'Shea JJ Nerenberg MI Constitutive activation of different Jak tyrosine kinases in human T cell leukemia virus type 1 (HTLV-1) Tax protein or virus-transformed cells.J Clin Invest. 1995; 96: 1548-1555Crossref PubMed Scopus (103) Google Scholar, 35Zhang Q Nowak I Vonderheid EC Rook AH Kadin ME Nowell PC Shaw LM Wasik MA Activation of Jak/STAT proteins involved in signal transduction pathway mediated by receptor for interleukin 2 in malignant T lymphocytes derived from cutaneous anaplastic large T-cell lymphoma and Sezary syndrome.Proc Natl Acad Sci USA. 1996; 93: 9148-9153Crossref PubMed Scopus (197) Google Scholar raising the possibility that an unbalanced, permanently turned-on IL-2R/Jak signaling leads to uncontrolled growth of these cells and may play a role in the pathogenesis of various types of human T cell malignancy. Lack of expression of SHP-1 protein has recently been identified in several HTLV-I-positive T cell lines.7Migone TS Calacano NA Migone TS Cacalano NA Taylor N Yi T Waldmann TA Johnston JA Recruitment of SH2-containing protein tyrosine phosphatase SHP-1 to the interleukin 2 receptor; loss of SHP-1 expression in human T-lymphotropic virus type I-transformed T cells.Proc Natl Acad Sci USA. 1998; 95: 3845-3850Crossref PubMed Scopus (112) Google Scholar, 36Zhang Q Lee B Korecka M Li G Weyland C Eck S Gessain A Arima N Shaw L Luger S Kamoun M Wasik MA Differences in phosphorylation of the IL-2R associated Jak/STAT proteins between HTLV-I(+), IL-2-independent and IL-2-dependent cell lines and uncultured leukemic cells from patients with adult T-cell lymphoma/leukemia (ATLL).Leuk Res. 1999; 23: 373-384Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar This observation combined with the presence of constitutive activation of the IL-2R Jak/STAT signaling pathway, suggested that the concomitant lack of SHP-1 protein may be responsible in some instances for the unbalanced IL-2R/Jak signaling. However, the extent of the loss of SHP-1 expression in T cell lymphomas, the mechanism of such loss and the exact effect of SHP-1 on the constitutive IL-2R/Jak signaling in malignant T cells remained undefined. Here we describe that lack of SHP-1 expression is frequent in T cell lymphomas and results from a transcriptional block of SHP-1 gene because of an extensive methylation of its promoter. Most, but not all, of the malignant T cell lines analyzed display constitutive activation of the IL-2R-associated Jak/STAT pathway. Reversal of the promoter methylation resulted in these cells in expression of SHP-1 mRNA and, less frequently, SHP-1 protein. The induced expression of SHP-1 protein correlated with dephosphorylation of the IL-2R-associated Jak3 kinase. These data demonstrate that inhibition of SHP-1 expression in malignant T cells is mediated by methylation of the SHP-1 gene promoter. Furthermore, they indicate that promoter methylation-induced transcriptional silencing of the SHP-1 gene may play a role in malignant T cell transformation by permitting persistent activation of the IL-2R/Jak signaling pathway and, possibly, other pathways regulated by SHP-1. Most cell lines used in this study were described in detail previously.35Zhang Q Nowak I Vonderheid EC Rook AH Kadin ME Nowell PC Shaw LM Wasik MA Activation of Jak/STAT proteins involved in signal transduction pathway mediated by receptor for interleukin 2 in malignant T lymphocytes derived from cutaneous anaplastic large T-cell lymphoma and Sezary syndrome.Proc Natl Acad Sci USA. 1996; 93: 9148-9153Crossref PubMed Scopus (197) Google Scholar, 36Zhang Q Lee B Korecka M Li G Weyland C Eck S Gessain A Arima N Shaw L Luger S Kamoun M Wasik MA Differences in phosphorylation of the IL-2R associated Jak/STAT proteins between HTLV-I(+), IL-2-independent and IL-2-dependent cell lines and uncultured leukemic cells from patients with adult T-cell lymphoma/leukemia (ATLL).Leuk Res. 1999; 23: 373-384Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar In brief, three cell lines (PB-1, 2A, and 2B) were established from a patient with a progressive cutaneous T-cell lymphoproliferative disorder. The PB-1 cell line was obtained at a relatively early stage of the patient’s cutaneous T lymphoma whereas the 2A and 2B lines were established at a later, aggressive stage of the disease. All lines showed the same morphology, immunophenotype, T-cell receptor rearrangement, and cytogenetic abnormalities as the original, patient-derived malignant cells. Sez-4 line, kindly provided by T. Abrams (Hahnemann University), was derived from a patient with Sezary syndrome and also bears close morphological, phenotypic, and genotypic resemblance to the original tumor. ATL-2, C91PL, HUT102B, and C10MJ2 cell lines represent HTLV-I-related acute T cell lymphoma/leukemia. The SUDHL-1 line was derived from ALK+ T cell lymphoma. L540, HS455, HDLM, and KM-H2 were obtained from patients with Hodgkin’s lymphoma.37Drexler HG Recent results on the biology of Hodgkin and Reed-Sternberg cells. II. Continuous cell lines.Leuk Lymphoma. 1993; 9: 1-25Crossref PubMed Scopus (136) Google Scholar Whereas L540 and HDLM are of T cell origin as demonstrated by immunophenotyping and T-cell receptor gene rearrangement analysis, KM-H2 displays a B cell phenotype and genotype. We determined by flow cytometry that the HS445 cell line is also of B cell origin (kappa-restricted CD19+, CD20+, CD22+, CD23+, CD10+ B cells; MA Wasik, unpublished data). The exact nature of the HS445 line is uncertain. Although derived from a patient with Hodgkin’s lymphoma, this line may represent a nonmalignant Epstein-Barr virus-transformed lymphoblastoid B cell line (HG Drexler, personal communication). The healthy adults served as normal controls. Peripheral blood mononuclear cells (PBMC) were obtained from such individuals by centrifugation on Ficoll/Paque gradient. Phytohemagglutinin (PHA) blasts were obtained by stimulation of the PBMC with the mitogen. Cell lines and PHA-stimulated PBMC were cultured at 37°C with 5% CO2 in standard RPMI 1640 medium supplemented with 10% heat-inactivated fetal bovine serum, 1% penicillin/streptomycin/fungizone mixture, and 2 mmol/Ll-glutamine.35Zhang Q Nowak I Vonderheid EC Rook AH Kadin ME Nowell PC Shaw LM Wasik MA Activation of Jak/STAT proteins involved in signal transduction pathway mediated by receptor for interleukin 2 in malignant T lymphocytes derived from cutaneous anaplastic large T-cell lymphoma and Sezary syndrome.Proc Natl Acad Sci USA. 1996; 93: 9148-9153Crossref PubMed Scopus (197) Google Scholar Tissue sections of lymph nodes and skin were obtained from eight cases of advanced cutaneous T cell lymphoma which has undergone histologically documented transformation into a diffuse large-cell lymphoma. Before the large cell transformation the patients had a 1- to 8-year (median, 6.5 years) history of mycosis fungoides, tumor phase (1 patient), or Sezary syndrome (7 patients) diagnosed based on the combination of clinical features, biopsy and peripheral blood smear morphology, immunophenotyping, T-cell gene rearrangement, and cytogenetics. After the diagnosis of the large cell transformation most of the patients received combined chemotherapy with no or transient response; seven died within 4 to 15 months of the diagnosis. In SHP-1 protein expression induction experiments, cell lines were treated for 72 hours with 20 ng/ml of phorbol 12-myristate 13-acetate (PMA; Sigma Chemical CO., St. Louis, MO).38Uchida T Matozaki T Matsuda K Suzuki T Matozaki S Nakano O Wada K Konda Y Sakamoto C Kasuga M Phorbol ester stimulates the activity of a protein tyrosine phosphatase containing SH2 domains (PTP1C) in HL-60 leukemia cells by increasing gene expression.J Biol Chem. 1993; 268: 11845-11850Abstract Full Text PDF PubMed Google Scholar, 39Zhao Z Shen SH Fischer EH Phorbol ester-induced expression, phosphorylation, and translocation of protein-tyrosine-phosphatase 1C in HL-60 cells.Proc Natl Acad Sci USA. 1994; 91: 5007-5011Crossref PubMed Scopus (53) Google Scholar, 40Delibrias CC Floettmann JE Rowe M Fearon DT Down-regulated expression of SHP-1 in Burkitt lymphomas and germinal center B lymphocytes.J Exp Med. 1997; 186: 1575-1583Crossref PubMed Scopus (62) Google Scholar In some experiments Ionomycin (Calbiochem, La Jolla, CA) was added to PMA at 1 μg/ml. In SHP-1 promoter demethylation experiments, the cell lines were cultured with 5-deoxyazacytidine (Sigma) at 1 μmol/L for 5 days. These assays were performed as described.35Zhang Q Nowak I Vonderheid EC Rook AH Kadin ME Nowell PC Shaw LM Wasik MA Activation of Jak/STAT proteins involved in signal transduction pathway mediated by receptor for interleukin 2 in malignant T lymphocytes derived from cutaneous anaplastic large T-cell lymphoma and Sezary syndrome.Proc Natl Acad Sci USA. 1996; 93: 9148-9153Crossref PubMed Scopus (197) Google Scholar, 36Zhang Q Lee B Korecka M Li G Weyland C Eck S Gessain A Arima N Shaw L Luger S Kamoun M Wasik MA Differences in phosphorylation of the IL-2R associated Jak/STAT proteins between HTLV-I(+), IL-2-independent and IL-2-dependent cell lines and uncultured leukemic cells from patients with adult T-cell lymphoma/leukemia (ATLL).Leuk Res. 1999; 23: 373-384Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar In brief, the cells (10 to 15 × 106) were washed and lysed in ice-cold lysis buffer. In the Jak3 phosphorylation experiments the cells were exposed for 5 minutes to 500 U of IL-2 or medium alone before lysis. The lysates were centrifuged and supernatants were precleared with protein A-Sepharose (Sigma), incubated with SHP-1 or Jak3 antiserum (Santa Cruz Biotechnology, Santa Cruz, CA) and protein A-Sepharose, washed, boiled, separated on a 10% polyacrylamide-sodium dodecyl sulfate gel, and transferred electrophoretically to hybridization transfer membranes. The membranes were blocked with 2% bovine serum albumin in tris-buffered-saline/Tween 20 (TBST) buffer. To detect protein expression the membranes were incubated with the SHP-1 or Jak3 antiserum. To detect protein phosphorylation, the membranes were incubated with anti-phosphotyrosine mAb (4G10; Upstate Biotechnology, Lake Placid, NY). Next, the membranes were incubated with an appropriate secondary, peroxidase-conjugated Ab. Blots were developed using the enhanced chemiluminescence (ECL) reagents (Amersham Life Science, Arlington Heights, IL). The staining was performed on formalin-fixed, paraffin-embedded tissue sections of skin and lymph nodes involved by cutaneous T cell lymphoma, large-cell type using a standard streptavidin-biotin complex technique (Research Genetics, Huntsville, AL) and the following antibodies: CD3 and CD20 (L-26) (both from DAKO, Carpinteria, CA), Ki-67 (mib1; Immunotech, Westbrook, ME), and SHP-1 (Santa Cruz Technology). To detect SHP-1, heat-induced antigen retrieval was performed using Antigen Retrieval AR-10 solution (Biogenex, San Ramon, CA) and 20 minutes slide immersion into a 95°C water bath. Total cellular RNA was extracted by RNeasy Mini Handbook kit (Qiagen, Valencia, CA). For Northern analysis, 20 μg of total RNA samples were separated on 1% agarose-formaldehyde gels, transferred to Hybond-N+ membranes (Amersham), and hybridized with either a 563-bp or 1-kb α[32P]-dCTP-labeled, reverse transcriptase-polymerase chain reaction (RT-PCR) generated SHP-1 cDNA probe amplified from the catalytic domain of SHP-1. Hybridization with a 670-bp β-actin cDNA probe served as a control. RT-PCR was performed with 1 μg of total RNA in RT buffer mixture containing 200 U of SuperScript TM II reverse transcriptase (Life Technologies, Inc., Rockville, MD). RNase H (Promega, Piscataway, NJ) was added and cDNA was purified on Centri-Sep columns (Princeton Separations, Princeton, NJ). PCR was performed with 2 μl of cDNA in a PCR buffer mixture containing 2 U Taq polymerase (Life Technologies, Inc.) and, when developing probes for Northern blotting, 8 μCi α[32P]-dCTP (Amersham). The SHP-1-specific primers (see below) were designed based on the SHP-1 genomic DNA sequence from the GenBank database using an Oligo (National Biosciences, Plymouth, MN) computer program. The PCR reaction was performed at 94°C for 3 minutes, followed by 30 cycles: 45 seconds at 94°C, 30 seconds at 57°C, and 1.5 minutes at 72°C. The amplified products were visualized in UV light by staining with ethidium bromide after electrophoresis in the 1.5% agarose gel. Genomic DNA extraction was performed with 2 × 107 cells using Qiagen Genomic DNA kit (Qiagen). For PCR, DNA was digested with methylation sensitive restriction enzymes (Hpa II, Eag I or Nae I; New England Biolabs, Beverly, MA) for 4 hours at 37°C. PCR was performed with primers which cover SHP-1 promoter 2 to exon 3 region (see below). For Southern blotting, DNA was digested with Mob I and the methylation-sensitive enzymes. The DNA digests were purified by phenol/chloroform extraction, ethanol precipitated, separated on 0.8% agarose gel, and blotted on Hybond N+ nylon membranes. The membrane-bound DNA was hybridized to 50 ng of the digoxigenin-labeled, PCR-generated SHP-1 DNA probe. Membranes were washed in buffer containing 0.2× standard saline citrate, 0.1% sodium dodecyl sulfate twice at 24°C and once at 68°C and exposed to autoradiographic film. To determine the nucleic acid sequence of the SHP-1 genomic DNA, we used the seven primer pairs to cover the entire gene region used by hematopoietic cells spanning from promoter 2 (P2) to exon 16 (E16). The primers were designed to include ∼60 to 80 bp of exon adjacent intronic DNA containing splice junction sequences. The primer pairs and DNA sequences analyzed were as follows: 1) 5′-cactgcagctgactcactgat and 5′-acggggaaccaggaatgagtg (P50 -E50), 2) 5′-tgctgtgctctaaaacgagaa and 5′-gtggaaagggtggtaggttag (E1-E3), 3) 5′-cacagtaggtgcttgatttcc and 5′-gggtggagacctgtgagatga (E4-E7), 4) 5′-cactccctccatacagatgat and 5′-agccctcagtttcccaacaag (E8-E9), 5) 5′-caggcactcagaacatagagc and 5′-aagaggaggaatggggagcac (E10-E11), 6) 5′-cggtgaccctgggcacattcc and 5′-gctacatctcatacacgagtg (E12-E14), and 7) 5′-gtccccctgtgctgtctcctg and 5′-actgtgcccgtcttatcgtca (E15-E16). The PCR amplification products were separated on agarose gel, visualized, and purified using the QIAEX gel purification kit (Qiagen). The nucleotide sequence of the PCR products was determined using ABI PRISM Ready Reaction Dye Deoxy Terminator Cycle Sequencing Kit (Perkin-Elmer, Emeryville, CA). The nucleotide sequence was determined on an automated ABI DNA sequencer (Applied Biosystems, Foster City, CA) and compared to the SHP-1 DNA sequence of a normal donor and the one available from GenBank. Previous studies7Migone TS Calacano NA Migone TS Cacalano NA Taylor N Yi T Waldmann TA Johnston JA Recruitment of SH2-containing protein tyrosine phosphatase SHP-1 to the interleukin 2 receptor; loss of SHP-1 expression in human T-lymphotropic virus type I-transformed T cells.Proc Natl Acad Sci USA. 1998; 95: 3845-3850Crossref PubMed Scopus (112) Google Scholar, 36Zhang Q Lee B Korecka M Li G Weyland C Eck S Gessain A Arima N Shaw L Luger S Kamoun M Wasik MA Differences in phosphorylation of the IL-2R associated Jak/STAT proteins between HTLV-I(+), IL-2-independent and IL-2-dependent cell lines and uncultured leukemic cells from patients with adult T-cell lymphoma/leukemia (ATLL).Leuk Res. 1999; 23: 373-384Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar have shown that most (five of seven) of the HTLV-I-positive T cell lines tested displayed either a lack or marked decrease in expression of the SHP-1 protein. To determine better the frequency of the SHP-1 protein loss in T cell malignancies, we analyzed seven additional T cell lines derived from various types of T cell lymphoma unrelated to the HTLV-I infection. These lymphomas represented aggressive types of non-Hodgkin’s T cell lymphoma and Hodgkin’s lymphoma with" @default.
• W2080411938 created "2016-06-24" @default.
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• W2080411938 creator A5018821561 @default.
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• W2080411938 date "2000-10-01" @default.
• W2080411938 modified "2023-10-09" @default.
• W2080411938 title "Lack of Phosphotyrosine Phosphatase SHP-1 Expression in Malignant T-Cell Lymphoma Cells Results from Methylation of the SHP-1 Promoter" @default.
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