Intrinsic and extrinsic mechanisms contribute to maintain the JAK/STAT pathway aberrantly activated in T-type large granular lymphocyte leukemia
| Autor: | Anna Cabrelle, Renato Zambello, Veronica Martini, Federica Frezzato, Antonella Teramo, Elisa Boscaro, Livio Trentin, Francesco Piazza, Cristina Gattazzo, Elisa Ave, Valentina Trimarco, Francesca Passeri, Albana Lico, Monica Facco, Gianpietro Semenzato, Giulia Tasca |
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| Rok vydání: | 2013 |
| Předmět: |
Male
STAT3 Transcription Factor Large granular lymphocytic leukemia Immunology Population Suppressor of Cytokine Signaling Proteins Biochemistry chemistry.chemical_compound medicine Humans SOCS3 Phosphorylation STAT3 education Cells Cultured Aged Janus Kinases education.field_of_study biology JAK-STAT signaling pathway Cell Biology Hematology Middle Aged medicine.disease Demethylating agent Leukemia Large Granular Lymphocytic STAT Transcription Factors Leukemia chemistry Suppressor of Cytokine Signaling 3 Protein Mutation Cancer research biology.protein Female Janus kinase Signal Transduction |
| Zdroj: | Blood. 121:3843-3854 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2012-07-441378 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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