ONCOGENIC ACTIVATION OF THE LCK PROTEIN ACCOMPANIES TRANSLOCATION OF THE LCK GENE IN THE HUMAN HSB2 T-CELL LEUKEMIA

The tyrosine protein kinase p56lck transduces signals important for an tigen-induced T-cell activation. In transgenic mice, p56lck is oncogen ic when overexpressed or expressed as a mutant, catalytically activate d enzyme. In humans, the LCK gene is located at the breakpoint of the t(1;7)(p34;q34) chromosomal translocation. This translocation position s the beta T-cell receptor constant region enhancer upstream of the LC K gene without interrupting the LCK coding sequences, and a translocat ion of this sort occurs in both the HSB2 and the SUP-T-12 T-cell lines . We have found that, although the level of the p56lck protein in HSB2 cells is elevated approximately 2-fold in comparison with that in nor mal T-cell lines, total cellular tyrosine protein phosphorylation is e levated approximately 10-fold. Increased levels of phosphotyrosine in HSB2 cells resulted from mutations in the LCK gene that activated its function as a phosphotransferase and converted it into a dominant tran sforming oncogene. The oncogenic p56lck in HSB2 cells contained one am ino acid substitution within the CD4/CD8-binding domain, two substitut ions in the kinase domain, and an insertion of Gln-Lys-Pro (QKP) betwe en the SH2 and kinase domains. In NIH 3T3 fibroblasts, three of these mutations cooperated to produce the fully oncogenic form of this p56lc k variant. These results suggest that mutation of LCK may contribute t o some human T-cell leukemias.