Coordinate change of c-myc, transferrin receptor and H3 gene expression precedes induction of haemoglobin-producing cells of the leukaemia K562 cell line treated with cis-diamminedichloroplatinum (II)

Abstract

Erythroid cell differentiation can be achieved in vitro by means of several chemical or natural agents. Cell differentiation is accompanied by biochemical and molecular changes which show that the inducer is active at different molecular levels. Among the chemical agents that are able to induce cell differentiation, the anticancer drugs are of great interest for the emerging study of in vitro and in vivo models for differentiation treatment. Cis-diamminedichloroplatinum II (CDDP), a crosslinking DNA compound, is usually employed at a high dosage in treating solid tumors. We have demonstrated that CDDP was also able to induce K562 cells towards erythroid differentiation. In our experiment 2.5 micrograms/ml of CDDP caused expression of alpha-globin chain gene and production of haemoglobulin. Continuous presence of the drug was not necessary to induce the cell to produce haemoglobin. Five days after CDDP treatment, the expression of c-myc oncogene had risen, while H3 histone mRNA expression fell to undetectable levels within 24 hours. Transferrin (Tf) receptor mRNA was reduced but later (about 48 hours) than c-myc and H3 messenger RNAs. The inhibition of cell proliferation was correlated both with the reduced expression of Tf receptor mRNA and low expression of the protein. However, expression of the cytoskeleton vimentin gene was only slightly affected during the time-course of the experiment. Data show that at least three phases were present in the irreversible CDDP induction of haemoglobin synthesis in the K562 cell. The erythroid differentiation was first preceded by a rise of c-myc mRNA, which probably precommits the cell towards the erythroid lineage. The mRNA levels of the cell-cycle dependent genes, H3 and Tf receptor, decreased and inhibition of DNA synthesis and loss of cell proliferation were detected. Finally, the alpha-globin chain gene was actively transcribed and the cell produced haemoglobin.