Expression of protein tyrosine kinases in the Ig complex of anti-mu-sensitive and anti-mu-resistant B-cell lymphomas: role of the p55blk kinase in signaling growth arrest and apoptosis.

The src family of non-receptor protein tyrosine kinases (PTKs), including the blk, fyn, lyn and lck kinases, is expressed in B-lineage cells, may associate with the immunoglobulin receptor complex and, therefore, play a role in signal transduction via membrane IgM. To establish which of these PTKs is involved in growth inhibition of B-cell lymphomas by anti-mu, we examined the expression pattern and state of activation of these kinases in nine B-cell lymphomas. Tyrosine-phosphorylated p55blk was constitutively expressed in all growth-inhibitable lymphomas; furthermore, anti-mu caused a relative increase of tyrosine phosphorylation in p55blk and a 2- to 3-fold increase in its kinase activity in these cells within minutes. In contrast, p55blk was not present in three of five anti-mu-resistant lymphomas and there was no detectable increase of blk activity in one of the resistant cell lines tested. Thus, we proposed that activatable blk kinase in the IgM complex is essential for the growth inhibitory effect of anti-mu. To test this hypothesis, CH31 lymphoma cells were treated with antisense oligos for the blk kinase and found to be resistant to anti-mu-mediated growth inhibition and subsequent apoptosis. These studies implicate the blk kinase as an integral part of the growth inhibitory pathway leading to arrest and apoptosis. Transfectants of blk gene constructs are being generated to further test this hypothesis.