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 th rough the activation of signal transducers and activators of transcription (STAT) proteins. An important step in the malignant progression of murine p lasmacytomas is the transition from dependence on IL-6 to a state of IL-6 i ndependence. To elucidate the mechanism whereby IL-6 independence occurs, i ntracellular signaling events elicited by IL-6 in both IL-6-dependent and - independent plasmacytomas and hybridomas were compared. It was found that S TAT3, a key molecule involved in IL-6 signaling, was constitutively activat ed and phosphorylated in IL-6-independent cell lines compared to the IL-6-d ependent cells. Further comparison of up stream signaling pathways revealed that JAK-1 was constitutively present in antiphosphotyrosine immunoprecipi tates of IL-6-independent cells; gp180 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 exogeno us IL-6, Secretion of a factor capable of supporting the growth of IL-6-dep endent cells was observed in one of the IL-6-independent plasmacytomas, but not in others, making an autocrine mechanism an unlikely explanation for I L-6 independence. These findings provide evidence that the constitutive act ivation of STAT3, either in the absence of detectable receptor-proximal eve nts or associated with the concomitant activation of gp130, can contribute to the process of IL-6 independence. (C) 2000 by The American Society of He matology.