Effects of tumor promoters on the expression of a tumor-related multigenic set in human cells.

We previously found that a minor subfraction of the human genomic DNA, corresponding to 2500-3000 nonrepetitive sequences of 3 kilobases each and designated as tumor-activated DNA (TaDNA) was transcriptionally active in Burkitt's lymphoma cells and almost inactive in normal lymphocytes growing in vitro following integration of the Epstein-Barr virus genome. Furthermore all the neoplastic cells in culture or primary neoplasms (leukemias, sarcomas, carcinomas) studied contained transcripts from most of the TaDNA sequences found in malignant lymphoblasts whereas normal cells growing in vitro contained only a few TaDNA transcripts. It is shown in the present study that treatments of the myeloid leukemia HL60 cells with various inducers of cell differentiation (dimethyl sulfoxide, retinoic acid, mezerein, 12-O-tetradecanoylphorbol-13-acetate, teleocidin) caused a dose-dependent reduction of the level of TaDNA transcripts, correlated with the diminution of c-myc transcripts. The 12-O-tetradecanoylphorbol-13-acetate treatment had this same effect on Burkitt's lymphoma cells (Raji or Namalwa) but the opposite effect on normal cells (Epstein-Barr virus-immortalized lymphocytes or fetal fibroblasts) where it enhanced the formation of Ta-DNA transcripts up to the levels found in untreated malignant cells. These data suggest two conclusions (a) TaDNA corresponds to a multigenic set which seems to be involved in modulation of the malignant phenotype and (b) depending on the origin of the cells, agents like 12-O-tetradecanoylphorbol-13-acetate may operate either as tumor promoters or as differentiation inducers through the control of TaDNA expression.