title: IL-21 contributes to JAK3/STAT3 activation and promotes cell growth in ALK-positive anaplastic large cell lymphoma.
abstract: Interleukin (IL)-21 has been reported to both stimulate cell growth and promote survival in benign lymphoid cells and several types of hematopoietic neoplasms. It induces JAK3/STAT3 signaling, a biologically important cellular pathway activated in most cases of anaplastic lymphoma kinase (ALK)-expressing anaplastic large cell lymphoma (ALK(+)ALCL). Therefore, we hypothesize that IL-21 may contribute to JAK3/STAT3 activation and cell growth in ALK(+)ALCL. By reverse transcription-PCR, we found consistent expression of IL-21 receptor (IL-21R) in all ALK(+)ALCL cell lines and frozen tumors examined. IL-21 was also consistently expressed in ALK(+)ALCL tumors, although its mRNA was detectable in only one of three cell lines tested. By immunohistochemistry, we examined 10 paraffin-embedded ALK(+)ALCL tumors; all cases were positive for both IL-21 and IL-21R in these neoplastic cells. IL-21 signaling is biologically significant in ALK(+)ALCL since the addition of recombinant IL-21 enhanced the activation of JAK3/STAT3 and significantly increased cell growth in ALK(+)ALCL cell lines. However, small interfering RNA down-regulation of IL-21R significantly decreased both STAT3 activation and cell growth. IL-21R expression is not linked to nucleophosmin-ALK since forced expression of nucleophosmin-ALK and small interfering RNA down-regulation of nucleophosmin-ALK did not significantly change the expression of either IL-21R or IL-21. Our findings thus support the enhancement of JAK3/STAT3 activation and cell growth in ALK(+)ALCL via IL-21 signaling. These results further support the concept that constitutive activation of STAT3 in these tumors is multifactorial.
authors.affiliation: Department of Laboratory Medicine and Pathology, Cross Cancer Institute and University of Alberta, 11560 University Avenue, Edmonton, Alberta, Canada T6G 1Z2.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dien Bard
authors.forename: Pascal
authors.initials: P
authors.lastname: Gelebart
authors.forename: Mona
authors.initials: M
authors.lastname: Anand
authors.forename: Zoulika
authors.initials: Z
authors.lastname: Zak
authors.forename: Samar A
authors.initials: SA
authors.lastname: Hegazy
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Amin
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D053616:Janus Kinase 3 / Q000096:biosynthesis*; D017728:Lymphoma, Large-Cell, Anaplastic / Q000201:enzymology / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000032:analysis; D034741:RNA, Small Interfering / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases; D053655:Receptors, Interleukin-21 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000096:biosynthesis*; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D034741:RNA, Small Interfering; D053655:Receptors, Interleukin-21; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3; D000098546:Interleukin-21