DEREGULATED C-MYC EXPRESSION IS INSUFFICIENT FOR EMERGENCE OF THE TUMORIGENIC PHENOTYPE IN MALIGNANCY-SUPPRESSED INTRATYPIC T-CELL LYMPHOMAHYBRIDS - AN IN-VITRO MODEL FOR MULTISTEP LYMPHOMAGENESIS

The T-cell lymphoma cell line YACUT was fused with the Mls-1(a) antige n-responsive non-tumorigenic T-cell line G4 to construct growth-arrest ed hybrids which could be induced to proliferate in the presence of Ml s-1(a) antigen. Prolonged growth of the hybrids by repeated antigenic stimulation resulted in the emergence of cells with transformed phenot ype, which was accompanied by a reversion of c-myc expression to the l evels of the YACUT lymphoma parent and an increase in the number of YA CUT-derived chromosome 15 carrying the rearranged pvt-1 gene. Despite these two changes, early passage transformed hybrids as well as prolif eration-suppressed hybrids were non-tumorigenic in vivo. The fact that only late passage transformed hybrids produced tumors in vivo indicat ed that additional genetic and/or epigenetic alterations are required for the emergence of hybrid lines with tumorigenic phenotype. Thus, th is experimental system offers tangible possibilities for delineation o f the three distinct phenotypes which could be exploited for the inves tigation of the multistep process of lymphomagenesis.