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Blood, 15 November 2000, Vol. 96, No. 10, pp. 3514-3521
IMMUNOBIOLOGY
Constitutive activation of STAT3 is associated with the
acquisition of an interleukin 6-independent phenotype by murine
plasmacytomas and hybridomas
Rashmi Rawat,
G. Jonah Rainey,
Cynthia D. Thompson,
Michelle R. Frazier-Jessen,
Robert T. Brown, and
Richard P. Nordan
From the Laboratory of Immunobiology, Division of
Monoclonal Antibodies, Center for Biologics Evaluation and Research,
Bethesda, MD.
Interleukin 6 (IL-6), the major growth factor for myeloma
cells, signals through the activation of signal transducers and activators of transcription (STAT) proteins. An important step in the
malignant progression of murine plasmacytomas is the transition from
dependence on IL-6 to a state of IL-6 independence. To elucidate the
mechanism whereby IL-6 independence occurs, intracellular signaling
events elicited by IL-6 in both IL-6-dependent and -independent plasmacytomas and hybridomas were compared. It was found that STAT3, a
key molecule involved in IL-6 signaling, was constitutively activated
and phosphorylated in IL-6-independent cell lines compared to the
IL-6-dependent cells. Further comparison of upstream signaling pathways revealed that JAK-1 was constitutively present in
anti-phosphotyrosine immunoprecipitates of IL-6-independent cells;
gp130 was constitutively phosphorylated in a subset of
IL-6-independent plasmacytomas, whereas other IL-6-independent lines
showed no detectable gp130 phosphorylation in the absence of exogenous
IL-6. Secretion of a factor capable of supporting the growth of
IL-6-dependent cells was observed in one of the IL-6-independent
plasmacytomas, but not in others, making an autocrine mechanism an
unlikely explanation for IL-6 independence. These findings provide
evidence that the constitutive activation of STAT3, either in the
absence of detectable receptor-proximal events or associated with the
concomitant activation of gp130, can contribute to the process of IL-6 independence.
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