Intrinsic and Estrinsic Mechanism Contributes to Maintain the JAK/STAT Pathway Aberrantly Activated in T-Type Large Granular Lymphocyte Leukemia

• Published in: Blood 2011-11, Vol.118 (21), p.1375-1375
• Main Authors: Zambello, Renato, Teramo, Antonella, Gattazzo, Cristina, Passeri, Francesca, Lico, Albana, Tasca, Giulia, Cabrelle, Anna, Frezzato, Federica, Martini, Veronica, Trimarco, Valentina, Berno, Tamara, Boscaro, Elisa, Facco, Monica, Trentin, Livio, Semenzato, Gianpietro
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V118.21.1375.1375

Abstract 1375 T-cell large granular lymphocyte (T-LGL) leukemia is a heterogeneous disorder characterized by the chronic expansion of a terminally differentiated cytotoxic T lymphocytes (CTLs) with a CD3+/CD8+/CD57+ phenotype. Although the pathogenesis of T-LGL leukemia is still unknown, the hallmark of the disease is the abnormal clonal expansion of antigen-primed mature CTLs that successfully escape activation-induced cell death (AICD) and remain long-term competent. Similar to normal activated CTLs, leukemic T-LGLs exhibit activation of multiple survival signaling pathways. Among the intracellular signaling pathways altered in T-LGL leukemia, JAK/STAT (Janus Kinase/signal transducer and transcription factor) signaling has been associated with LGL transformation. In particular, it has been demonstrated that the STAT3, a pivotal element of this pathway, is over-expressed and constitutively activated in leukemic LGLs as compared to normal peripheral blood mononuclear cells (PBMCs). STAT3 is a transcription factor inducing a number of genes promoting cell survival and the involvement of an aberrant STAT3 expression has been suggested to play a role in the pathogenesis of this disease. In order to investigate the mechanism through which STAT3 is maintained in a state of activation in T-LGL leukemia, in patients in 27 patients we studied the expression of “suppressor of cytokine signaling 3 protein” (SOCS3) which is the specific negative regulator of STAT3 signaling, and the interleukin 6 (IL-6), which strongly induces STAT3 activation. Expression analysis was performed by Real Time-PCR and Western Blot assay in highly purified LGLs from PBMCs of patients by magnetic microbeads system. By Real Time-PCR, the expression level of IL-6 was shown to be increased in patients’ PBMCs (56.84 ± 17.01) as compared to normal PBMCs (0.53 ± 0.14, p