Role of phosphatidylinositol 3-kinase in anti-IgM-and anti-IgD-induced apoptosis in B cell lymphomas

Cross-linking of surface Ig receptors with anti IgM (anti-μ heavy chain, anti-μ), but not anti-IgD (anti-δ heavy chain, anti-δ), 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-δ 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 phospholiplds below control with time, which is followed by p27^Kip1 induction. Conversely, anti-δ, but not anti-μ stimulated PI3K-dependent phosphollpid 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-δ 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-δ) determines B cell fate.