Intrinsic and extrinsic mechanisms contribute to maintain the JAK/STAT pathway aberrantly activated in T-type large granular lymphocyte leukemia

• Published in: Blood 2013-05, Vol.121 (19), p.3843-3854
• Main Authors: Teramo, Antonella, Gattazzo, Cristina, Passeri, Francesca, Lico, Albana, Tasca, Giulia, Cabrelle, Anna, Martini, Veronica, Frezzato, Federica, Trimarco, Valentina, Ave, Elisa, Boscaro, Elisa, Piazza, Francesco, Facco, Monica, Trentin, Livio, Semenzato, Gianpietro, Zambello, Renato
• Format: Article
• Language: English
• Subjects: Aged; Cells, Cultured; Female; Humans; Janus Kinases - genetics; Janus Kinases - metabolism; Leukemia, Large Granular Lymphocytic - genetics; Leukemia, Large Granular Lymphocytic - metabolism; Male; Middle Aged; Mutation - physiology; Phosphorylation; Signal Transduction - genetics; Signal Transduction - physiology; STAT Transcription Factors - genetics; STAT Transcription Factors - metabolism; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - genetics; Suppressor of Cytokine Signaling Proteins - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-07-441378

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. •In T-LGLL, autologous LGL-depleted PBMCs release high levels of IL-6 contributing to the constitutive STAT3 activation in leukemic LGL.•Leukemic LGLs show SOCS3 down-modulation, which is responsible for lack of the negative feedback mechanism controlling STAT3 activation.