Constitutive activation of STAT3 is associated with the acquisition of an interleukin 6-independent phenotype by murine plasmacytomas and hybridomas

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.