Constitutive STAT6 activation in primary mediastinal large B-cell lymphoma

Primary mediastinal large B-cell lymphoma (PMBL), currently recognized as a diffuse large B-cell lymphoma (DLBCL) subtype, shows increased expression of interleukin 4 (IL-4)/IL-13 signaling effectors and targets, suggesting constitutive activation of these pathways. We therefore investigated the fun...

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Veröffentlicht in:Blood 2004-07, Vol.104 (2), p.543-549
Hauptverfasser: Guiter, Chrystelle, Dusanter-Fourt, Isabelle, Copie-Bergman, Christiane, Boulland, Marie-Laure, le Gouvello, Sabine, Gaulard, Philippe, Leroy, Karen, Castellano, Flavia
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container_end_page 549
container_issue 2
container_start_page 543
container_title Blood
container_volume 104
creator Guiter, Chrystelle
Dusanter-Fourt, Isabelle
Copie-Bergman, Christiane
Boulland, Marie-Laure
le Gouvello, Sabine
Gaulard, Philippe
Leroy, Karen
Castellano, Flavia
description Primary mediastinal large B-cell lymphoma (PMBL), currently recognized as a diffuse large B-cell lymphoma (DLBCL) subtype, shows increased expression of interleukin 4 (IL-4)/IL-13 signaling effectors and targets, suggesting constitutive activation of these pathways. We therefore investigated the functional state of the signal transducer and activator of transcription 6 (STAT6), mediating IL-4/IL-13 transcriptional effects. Constitutive STAT6 phosphorylation and DNA-binding activity were detected in PMBL cell lines but not DLBCL cell lines. Moreover, immunohistochemical analysis revealed nuclear phosphorylated STAT6 (P-STAT6) in 8 of 11 PMBL, compared with 1 of 10 DLBCL primary tumors (P = .01). IL-4 and IL-13 transcripts were absent in PMBL cell lines and expressed at low levels in tumors, indicating that, contrary to classical Hodgkin lymphoma (cHL), STAT6 activation is not due to an autocrine IL-4/IL-13 secretion. We demonstrated an amplification of the JAK2 gene in 2 of 6 PMBL cases, and showed higher JAK2 mRNA levels in PMBL compared with DLBCL (P = .005). The Janus kinase 2 (JAK2) was constitutively phosphorylated in the PMBL MedB1 cell line. MedB1 treatment with JAK2 inhibitor AG490 partially decreased STAT6 phosphorylation, suggesting that JAK2 is partially involved in STAT6 activation in these cells. Our findings highlight phosphorylated STAT6 as a characteristic distinguishing PMBL from DLBCL, but a common feature to PMBL and cHL, supporting the hypothesis of common pathogenic events in these 2 lymphomas. (Blood. 2004;104: 543-549)
doi_str_mv 10.1182/blood-2003-10-3545
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Myelofibrosis</topic><topic>Lymphoma, B-Cell - metabolism</topic><topic>Lymphoma, B-Cell - physiopathology</topic><topic>Lymphoma, Large B-Cell, Diffuse - metabolism</topic><topic>Lymphoma, Large B-Cell, Diffuse - physiopathology</topic><topic>Mediastinal Neoplasms - metabolism</topic><topic>Mediastinal Neoplasms - physiopathology</topic><topic>Medical sciences</topic><topic>Phosphorylation</topic><topic>Protein-Tyrosine Kinases - metabolism</topic><topic>Proto-Oncogene Proteins</topic><topic>STAT6 Transcription Factor</topic><topic>Trans-Activators - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Guiter, Chrystelle</creatorcontrib><creatorcontrib>Dusanter-Fourt, Isabelle</creatorcontrib><creatorcontrib>Copie-Bergman, Christiane</creatorcontrib><creatorcontrib>Boulland, Marie-Laure</creatorcontrib><creatorcontrib>le Gouvello, Sabine</creatorcontrib><creatorcontrib>Gaulard, Philippe</creatorcontrib><creatorcontrib>Leroy, Karen</creatorcontrib><creatorcontrib>Castellano, Flavia</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Guiter, Chrystelle</au><au>Dusanter-Fourt, Isabelle</au><au>Copie-Bergman, Christiane</au><au>Boulland, Marie-Laure</au><au>le Gouvello, Sabine</au><au>Gaulard, Philippe</au><au>Leroy, Karen</au><au>Castellano, Flavia</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Constitutive STAT6 activation in primary mediastinal large B-cell lymphoma</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2004-07-15</date><risdate>2004</risdate><volume>104</volume><issue>2</issue><spage>543</spage><epage>549</epage><pages>543-549</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><abstract>Primary mediastinal large B-cell lymphoma (PMBL), currently recognized as a diffuse large B-cell lymphoma (DLBCL) subtype, shows increased expression of interleukin 4 (IL-4)/IL-13 signaling effectors and targets, suggesting constitutive activation of these pathways. 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subjects Biological and medical sciences
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Hematologic and hematopoietic diseases
Humans
Interleukin-13 - genetics
Interleukin-4 - genetics
Janus Kinase 2
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Lymphoma, B-Cell - metabolism
Lymphoma, B-Cell - physiopathology
Lymphoma, Large B-Cell, Diffuse - metabolism
Lymphoma, Large B-Cell, Diffuse - physiopathology
Mediastinal Neoplasms - metabolism
Mediastinal Neoplasms - physiopathology
Medical sciences
Phosphorylation
Protein-Tyrosine Kinases - metabolism
Proto-Oncogene Proteins
STAT6 Transcription Factor
Trans-Activators - metabolism
title Constitutive STAT6 activation in primary mediastinal large B-cell lymphoma
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