title: IL-2R common gamma-chain is epigenetically silenced by nucleophosphin-anaplastic lymphoma kinase (NPM-ALK) and acts as a tumor suppressor by targeting NPM-ALK.
abstract: Anaplastic lymphoma kinase (ALK), physiologically expressed only by certain neural cells, becomes highly oncogenic, when aberrantly expressed in nonneural tissues as a fusion protein with nucleophosphin (NPM) and other partners. The reason why NPM-ALK succeeds in transforming specifically CD4(+) T lymphocytes remains unknown. The IL-2R common γ-chain (IL-2Rγ) is shared by receptors for several cytokines that play key roles in the maturation and growth of normal CD4(+) T lymphocytes and other immune cells. We show that IL-2Rγ expression is inhibited in T-cell lymphoma cells expressing NPM-ALK kinase as a result of DNA methylation of the IL-2Rγ gene promoter. IL-2Rγ promoter methylation is induced in malignant T cells by NPM-ALK. NPM-ALK acts through STAT3, a transcription factor that binds to the IL-2Rγ gene promoter and enhances binding of DNA methyltransferases (DNMTs) to the promoter. In addition, STAT3 suppresses expression of miR-21, which selectively inhibits DNMT1 mRNA expression. Reconstitution of IL-2Rγ expression leads to loss of the NPM-ALK protein and, consequently, apoptotic cell death of the lymphoma cells. These results demonstrate that the oncogenic tyrosine kinase NPM-ALK induces epigenetic silencing of the IL-2Rγ gene and that IL-2Rγ acts as a tumor suppressor by reciprocally inhibiting expression of NPM-ALK.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. qian2@mail.med.upenn.edu
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Hong Yi
authors.initials: HY
authors.lastname: Wang
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Liu
authors.forename: Gauri
authors.initials: G
authors.lastname: Bhutani
authors.forename: Kanchan
authors.initials: K
authors.lastname: Kantekure
authors.forename: Mariusz
authors.initials: M
authors.lastname: Wasik
mesh_terms: D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D017931:DNA Primers / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D020868:Gene Silencing; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics* / Q000378:metabolism*; D008156:Luciferases; D020411:Oligonucleotide Array Sequence Analysis; D010957:Plasmids / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; C507941:IL2RG protein, human; D053631:Interleukin Receptor Common gamma Subunit; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D025521:Tumor Suppressor Proteins; D008156:Luciferases; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases