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Blood, 15 January 2002, Vol. 99, No. 2, pp. 618-626
NEOPLASIA
Signal transducer and activator of transcription 6 is frequently
activated in Hodgkin and Reed-Sternberg cells of Hodgkin
lymphoma
Brian F. Skinnider,
Andrew
J. Elia,
Randy D. Gascoyne,
Bruce Patterson,
Lorenz Trumper,
Ursula Kapp, and
Tak W. Mak
From the Amgen Institute and Department of Oncologic
Pathology, Ontario Cancer Institute, Toronto, Canada; the Departments
of Medical Biophysics and Immunology, University of Toronto, Canada;
the Department of Pathology, British Columbia Cancer Agency, Vancouver,
Canada; the Department of Hematology/Oncology, Georg August University,
Göttingen, Germany; and the Department of Hematology/Oncology,
University Medical Center, Freiburg, Germany.
The unique clinicopathologic features of Hodgkin lymphoma (HL) are
due to the multiple cytokines produced by its neoplastic cells, the
Hodgkin and Reed-Sternberg (HRS) cells. Cytokine signaling is mediated
through the signal transducer and activator of transcription (STAT)
family of transcription factors. Immunoblotting and
immunohistochemistry were used to examine cell lines and tissue
sections derived from patients with HL and non-Hodgkin lymphoma (NHL)
for expression of activated STAT proteins. Constitutive phosphorylation
of STAT6 and STAT3 was common in HL. STAT6 was constitutively
phosphorylated in 5 of 5 HL cell lines and in HRS cells from 25 of 32 (78%) classical HL cases. STAT3 was constitutively phosphorylated in 4 of 5 HL cell lines and in HRS cells from 27 of 31 (87%) classical HL
cases. Only 4 of 24 NHL cases demonstrated constitutive STAT6
activation, whereas STAT3 activation was observed in 6 of 13 (46%)
cases of B-cell NHL and 8 of 11 (73%) cases of T-cell NHL.
Constitutive STAT5 phosphorylation was not a common feature of HL or
NHL. STAT6 mediates signaling by interleukin 13 (IL-13), a cytokine
frequently expressed by HRS cells. Antibody-mediated neutralization of
IL-13 resulted in significant decreases in both cellular proliferation and levels of phosphorylated STAT6 of HL cell lines. In conclusion, constitutive STAT6 phosphorylation is a common and distinctive feature
of HRS cells in classical HL, whereas STAT3 activation was regularly
present in both HL and NHL. These results suggest that IL-13 signaling
is largely responsible for the constitutive STAT6 activation observed
in HRS cells and further implicate IL-13 as an important growth factor
in classical HL.
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