ANTISENSE OLIGODEOXYNUCLEOTIDES TO THE BLK TYROSINE KINASE PREVENT ANTI-MU-CHAIN-MEDIATED GROWTH-INHIBITION AND APOPTOSIS IN A B-CELL LYMPHOMA

Crosslinking of membrane immunoglobulin (mIg) receptors by anti-Ig cau ses growth inhibition and subsequent cell death due to apoptosis in a murine B-cell lymphoma model. The earliest signal transduction via mIg has recently been shown to be dependent on the activation of one or m ore protein tyrosine kinases (PTKs). In this study, we utilized the CH 31 lymphoma, which is extremely sensitive to growth inhibition by anti -Ig, to examine the role of PTKs in cell cycle arrest. This cell line expresses multiple PTKs, whose activities are stimulated by crosslinki ng mIg. To determine whether PTK activity is essential for the inhibit ion of cell growth, we exposed CH31 cells to antisense oligodeoxynucle otides for the blk PTK prior to the growth inhibition assay. We found that exposure of CH31 cells to blk antisense effectively prevented ant i-mu-chain-mediated growth inhibition and subsequent apoptosis. Corres ponding blk sense or antisense oligonucleotides for other PTKs had no protective effect against anti-mu. Moreover, antisense blk oligonucleo tides had no effect on transforming growth factor beta-mediated growth arrest and apoptosis. Further experiments showed significantly reduce d endogenous p55blk in blk antisense-treated cells. In addition, anti- mu stimulation of antisense-treated cells failed to induce any detecta ble increase in kinase activity of p55blk, a result suggesting the unc oupling of blk proteins from normal signal pathways that are essential for growth inhibition. These results implicate a role of blk kinase i n anti-mu-mediated pathway to cell cycle arrest.