Life and death decisions in B1 lymphoma cells

Crosslinking of surface immunoglobulin (Ig) receptors with anti-IgM (anti-mu) but not anti-IgD (anti-delta) antibodies causes growth arrest and apoptosis in several extensively characterized B1-like lymphoma cell lines. While anti-mu stimulates a transient increase in c-myc mRNA and protein expression, followed by a rapid decline below the baseline level, anti-delta only causes a moderate increase in the expression of this oncogene, which returns to baseline levels within 24-48 hours. However, signals downstream from anti-delta can be converted into an apoptotic pathway by modulating PI3K activity, suggesting that PI3K is a critical rheostat controlling survival signals in B1 cell lines. Anti-mu -induced down-regulation of c-Myc is followed in time with an increase in the cyclin dependent kinase inhibitor, p27(Kip1), in all anti-mu sensitive lymphoma lines. This increase correlates with growth arrest and apoptosis. The anti-mu -mediated decrease in c-Myc, increase in p27(Kip1), growth arrest and apoptosis, can all be prevented via CD40/CD40L signaling. Inhibition of caspase activation, on the other hand, prevents anti-mu -induced apoptosis, but has no effect on c-Myc, p27(Kip1) and G1 arrest. Interestingly, we also found that steroids and retinoids can mimic anti-mu -mediated signaling and lead to a loss of c-Myc, an increase in p27(Kip1), G1 arrest, and apoptosis. Together, these data suggest that modulation of c-Myc and p27(Kip1) protein levels is crucial for the life versus death decisions in murine immature B1-like lymphoma cells lines.