The regulation of beta-lymphoma growth by antibodies directed at membrane IgM (anti-IgM) has been studies using a panel of murine B-cell lymphomas. Previous evidence in our laboratory indicates that anti-IGM antibodies are able to inhibit growth of these lymphomas at a point in early G1 such that these cells arrest near the G1:S interface, after which they undergo apoptosis and die. In these cells, the retinoblastoma growth suppressor gene product, pRB, is underphosphorylated in the presence of anti-IgM, in a manner that mimics the effects of TGF-beta. However, recent data suggest that this effect may be TGF-beta independent. We have recently demonstrated that this process is consequent to the modulation of c-myc and dependent on the activity of the blk tyrosine kinase gene product. During this grant , we propose to inhibit/modulate tyrosine kinase activity by anti-sense oligos and by transfection of different tyrosine kinase genes, either in a constitutively active or an inactive form. In addition, analysis of c-myc protein levels and localization (nuclear vs. cytoplasmic) will be performed in conjunction with establishing the kinetics of PRB phosphorylation events. These studies will provide information on neoplastic B-cell regulation and the role that these kinases and oncogenes/anti-oncogenes play in this process.
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