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Blood, 15 February 2001, Vol. 97, No. 4, pp. 1056-1062
NEOPLASIA
STAT3-mediated constitutive expression of SOCS-3 in cutaneous
T-cell lymphoma
Christine Brender,
Mette Nielsen,
Keld Kaltoft,
Gitte Mikkelsen,
Qian Zhang,
Mariusz Wasik,
Nils Billestrup, and
Niels Ødum
From the Institute of Medical Microbiology and
Immunology, University of Copenhagen, Copenhagen, Denmark; Institute of
Human Genetics, University of Aarhus, Aarhus, Denmark; Department of
Pathology and Laboratory Medicine, University of Pennsylvania Medical
Center, Philadelphia, PA; and Signal Transduction, Novo Nordisk
Discovery, Bagsværd, Denmark.
A characteristic feature of neoplastic transformation is the loss
of external control by cytokines and extracellular matrix of cellular
differentiation, migration, and mitogenesis. Because suppressors of
cytokine signaling (SOCS) proteins are negative regulators of
cytokine-induced signaling, it has been hypothesized that an aberrant
SOCS expression plays a role in neoplastic transformation. This study
reports on a constitutive SOCS-3 expression in cutaneous T-cell
lymphoma (CTCL) cell lines. SOCS-3 protein is constitutively expressed
in tumor cell lines (but not in nonmalignant T cells) obtained from
affected skin from a patient with mycosis fungoides (MF) and from
peripheral blood from a patient with Sezary syndrome (SS). In contrast,
constitutive SOCS-3 expression is not found in the leukemic Jurkat
T-cell line, the MOLT-4 acute lymphoblastic leukemia cell line, and the
monocytic leukemic cell line U937. Expression of SOCS-3 coincides with
a constitutive activation of STAT3 in CTCL tumor cells, and stable
transfection of CTCL tumor cells with a dominant negative STAT3
strongly inhibits SOCS-3 expression, whereas transfection with
wild-type STAT3 does not. Moreover, the reduced SOCS-3 expression in
cells transfected with the dominant negative STAT3 is associated with
an increased sensitivity to interferon- (IFN-). In conclusion,
evidence is provided for a constitutive SOCS-3 expression in cancer
cells obtained from patients with CTCL. Moreover, the findings indicate
that the aberrant expression of SOCS-3 is mediated by a constitutive
activation of STAT3 in CTCL cells and affects the IFN- sensitivity
of these cells.
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