CONSISTENT LOSS OF FUNCTIONAL TRANSFORMING-GROWTH-FACTOR-BETA RECEPTOR EXPRESSION IN MURINE PLASMACYTOMAS

Murine plasmacytomas are tumors of Ig-secreting plasma cells that can be induced in genetically susceptible BALB/c mice. The deregulation of the c-myc protooncogene is a critical oncogenic event in the developm ent of plasmacytomas (Pers) although it is not sufficient for their ma lignant transformation. We have demonstrated that PCTs produce active transforming growth factor beta (TGF-beta) in vitro. Because TGF-beta is a potent negative regulator of the proliferation and differentiatio n of B lymphocytes, we examined its role in plasmacytomagenesis by com paring responsiveness to TGF-beta of nonneoplastic plasma cells and PC Ts. The nontransformed plasma cells that accumulate in interleukin 6 t ransgenic mice undergo accelerated apoptosis upon treatment with TGF-b eta, but the 15 PCTs studied, including primary and transplanted tumor s as well as established cell lines, were refractory to TGF-beta-media ted growth inhibition and apoptosis, Although PCTs lack functional TGF -beta receptors as demonstrated by chemical crosslinking to radiolabel ed TGF-beta 1, they nonetheless contain mRNA and protein for both type I and II TGF-beta receptors, suggesting a potential defect in recepto r trafficking or processing. The results clearly show the consistent i nactivation of TGF-beta receptors in plasmacytoma cells, demonstrating for the first time that interruption of a tumor suppressor pathway co ntributes to plasmacytomagenesis.