title: Intrinsic and extrinsic mechanisms contribute to maintain the JAK/STAT pathway aberrantly activated in T-type large granular lymphocyte leukemia.
abstract: The JAK/STAT pathway is altered in T-cell large granular lymphocytic leukemia. In all patients, leukemic LGLs display upregulation of phosphorylated STAT3 (P-STAT3) that activates expression of many antiapoptotic genes. To investigate the mechanisms maintaining STAT3 aberrantly phosphorylated using transcriptional protein and functional assays, we analyzed interleukin (IL)-6 and suppressor of cytokine signaling-3 (SOCS3), 2 key factors of the JAK/STAT pathway that induce and inhibit STAT3 activation, respectively. We showed that IL-6 was highly expressed and released by the patients' peripheral blood LGL-depleted population, accounting for a trans-signaling process. By neutralizing IL-6 or its specific receptor with specific antibodies, a significant reduction of P-STAT3 levels and, consequently, LGL survival was demonstrated. In addition, we found that SOCS3 was down-modulated in LGL and unresponsive to IL-6 stimulation. By treating neoplastic LGLs with a demethylating agent, IL-6-mediated SOCS3 expression was restored with consequent P-STAT3 and myeloid cell leukemia-1 down-modulation. Methylation in the SOCS3 promoter was not detectable, suggesting that an epigenetic inhibition mechanism occurs at a different site. Our data indicate that loss of the inhibitor SOCS3 cooperates with IL-6 to maintain JAK/STAT pathway activation, thus contributing to leukemic LGL survival, and suggest a role of demethylating agents in the treatment of this disorder.
authors.affiliation: Padua University School of Medicine, Department of Medicine, Hematology and Clinical Immunology Branch, University of Padua, Padua, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Teramo
authors.forename: Cristina
authors.initials: C
authors.lastname: Gattazzo
authors.forename: Francesca
authors.initials: F
authors.lastname: Passeri
authors.forename: Albana
authors.initials: A
authors.lastname: Lico
authors.forename: Giulia
authors.initials: G
authors.lastname: Tasca
authors.forename: Anna
authors.initials: A
authors.lastname: Cabrelle
authors.forename: Veronica
authors.initials: V
authors.lastname: Martini
authors.forename: Federica
authors.initials: F
authors.lastname: Frezzato
authors.forename: Valentina
authors.initials: V
authors.lastname: Trimarco
authors.forename: Elisa
authors.initials: E
authors.lastname: Ave
authors.forename: Elisa
authors.initials: E
authors.lastname: Boscaro
authors.forename: Francesco
authors.initials: F
authors.lastname: Piazza
authors.forename: Monica
authors.initials: M
authors.lastname: Facco
authors.forename: Livio
authors.initials: L
authors.lastname: Trentin
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Semenzato
authors.forename: Renato
authors.initials: R
authors.lastname: Zambello
mesh_terms: D000368:Aged; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism*; D054066:Leukemia, Large Granular Lymphocytic / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D010766:Phosphorylation; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C106644:SOCS3 protein, human; D050791:STAT Transcription Factors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D053612:Janus Kinases