Fusion of the YACUT lymphoma cell line with the Mls-1a-antigen-specific non-tumorigenic T-cell line G4 produced growth-arrested hybrids that could be induced to proliferate in the presence of Mls-1a antigen. Prolonged growth of such hybrids by repeated antigenic stimulation resulted in the appearance of autonomously growing hybrid lines. Of the 4 antigen-independent hybrid clones, I was weakly tumorigenic (25% incidence) while the other 3 were highly tumorigenic (100% incidence). In the growth-arrested hybrids the de-regulated c-myc expression characteristic of the YACUT cells was suppressed. In the autonomously growing clones, however, c-myc expression had reverted to the levels of the lymphoma parent and 1 to 2 extra copies of chromosome 15 were consistently present. These results indicate that repeated antigenic stimulation somehow abrogated the down-regulation of c-myc in the growth-arrested hybrid lines. The increase in the number of copies of chromosome 15, however, suggests that genes located on this chromosome may abolish the effect of the negative regulatory functions of the non-malignant parent in a gene-dosage-dependent manner.