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Role of Phosphatidylinositol 3-Kinase in Anti-IgM- and Anti-IgD-Induced Apoptosis in B Cell Lymphomas^{1 ,2}

Department of Immunology, Holland Laboratory of the American Red Cross, Rockville, MD 20855

Cross-linking of surface Ig receptors with anti IgM (anti-µ heavy chain, anti-µ), but not anti-IgD (anti- heavy chain, anti-), Abs leads to growth arrest and apoptosis in several extensively characterized B cell lymphomas. By poorly understood mechanisms, both Igs transiently stimulate c-Myc protein expression. However, ultimately, only anti-µ causes a severe loss in c-Myc and a large induction of p27^Kip1 protein expression. Because phosphatidylinositol 3-kinase (PI3K) has been established as a major modulator of cellular growth and survival, we investigated its role in mediating anti-Ig-stimulated outcomes. Herein, we show that PI3K pathways regulate cell cycle progression and apoptosis in the ECH408 B cell lymphoma. Anti-µ and anti- driven c-Myc protein changes precisely follow their effects on the PI3K effector, p70^S6K. Upstream of p70^S6K, signaling through both Ig receptors depresses PI3K pathway phospholipids below control with time, which is followed by p27^Kip1 induction. Conversely, anti-, but not anti-µ stimulated PI3K-dependent phospholipid return to control levels by 4–8 h. Abrogation of the PI3K pathway with specific inhibitors mimics anti-µ action, potentiates anti-µ-induced cell death and, importantly, converts anti- to a death signal. Transfection with active PI3K kinase construct induces anti-µ resistance, whereas transfection with dominant negative PI3K augments anti-µ sensitivity. Our results show that prolonged disengagement of PI3K or down-regulation of its products by anti-µ (and not anti-) determines B cell fate.

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