STAT3-mediated constitutive expression of SOCS-3 in cutaneous T-cell lymphoma

A characteristic feature of neoplastic transformation is the loss of extern al control by cytokines and extracellular matrix of cellular differentiatio n, migration, and mitogenesis, Because suppressors of cytokine signaling (S OCS) proteins are negative regulators of cytokine-induced signaling, it has been hypothesized that an aberrant SOCS expression plays a role in neoplas tic transformation. This study reports on a constitutive SOCS-3 expression in cutaneous T-cell lymphoma (CTCL) cell lines. SOCS-3 protein is constitut ively expressed in tumor cell lines (but not in nonmalignant T cells) obtai ned from affected skin from a patient with mycosis fungoides (MF) and from peripheral blood from a patient with Sezary syndrome (SS). In contrast, con stitutive SOCS-3 expression is not found in the leukemic Jurkat T-cell line , the MOLT-4 acute lymphoblastic leukemia cell line, and the monocytic leuk emic cell line U937. Expression of SOCS-3 coincides with a constitutive act ivation of STATE in CTCL tumor cells, and stable transfection of CTCL tumor cells with a dominant negative STATE strongly inhibits SOCS-3 expression, whereas transfection with wildtype STAT3 does not. Moreover, the reduced SO CS-3 expression in cells transfected with the dominant negative STAT3 Is as sociated with an increased sensitivity to interferon-alpha (IFN-alpha). In conclusion, evidence is provided for a constitutive SOCS-3 expression in ca ncer cells obtained from patients with CTCL. Moreover, the findings indicat e that the aberrant expression of SOCS-3 is mediated by a constitutive acti vation of STATE in CTCL cells and affects the IFN-alpha sensitivity of thes e cells. (C) 2001 by The American Society of Hematology.