LINEAGE-SPECIFIC INDUCTION OF B-CELL APOPTOSIS AND ALTERED SIGNAL-TRANSDUCTION BY THE PHOSPHOTYROSINE PHOSPHATASE INHIBITOR BIS(MALTOLATO)OXOVANADIUM(IV)

Protein tyrosine phosphorylation is known to play key roles in lymphoc yte signal transduction, and phosphotyrosine phosphatases (PTP) can ac t as both positive and negative regulators of these lymphocyte signals . We sought to examine the role of PTP further in these processes by c haracterizing the effects of bis(maltolato)oxovanadium(IV) (BMLOV), pr eviously known to be a nontoxic insulin mimetic agent in vivo. BMLOV w as found to be a potent phosphotyrosine phosphatase inhibitor. BMLOV i nduced cellular tyrosine phosphorylation in B cells in a pattern simil ar to that observed following antigen receptor stimulation, whereas li ttle tyrosine phosphorylation was induced in T cells. In B cells, BMLO V treatment resulted in tyrosine phosphorylation of Syk and phospholip ase C gamma(2), while sIgM-induced signals were inhibited. By contrast , T cell receptor signals were moderately increased by BMLOV, and the cells displayed greater induction of IL-2 receptor without toxicity. T he compound selectively induced apoptosis in B cell lymphoma and myelo id leukemia cell lines, but not in T cell leukemia or colon carcinoma cells. Interleukin-4 plus anti-CD40 antibody treatment of normal human peripheral B cells rescued the cells from BMLOV-induced death. These results suggest that phosphotyrosine phosphatase inhibitors can activa te B cell signal pathways in a lineage-specific manner, resulting in d esensitization of receptor-mediated signaling and induction of apoptos is.