DIFFERENTIATION OF WEHI-3B D+ MYELOMONOCYTIC LEUKEMIA-CELLS INDUCED BY ECTOPIC EXPRESSION OF THE PROTOONCOGENE C-JUN

The product of the protooncogene c-jun is one of the components of the AP-1 transcription factor complex, which is involved in the control of cell proliferation and differentiation. To study the role of c-jun in leukemia cell growth and maturation, a plasmid (pMTJ11) was constructed that contained the rat c-jun complementary DNA under the control of the human metallothionein promoter and the neo gene. Murine myelomonocytic WEHI-3B D+ cells were transfected by electroporation with the linearized pMTJ11 plasmid and subsequently cloned in the presence of G-418. Exposure of these clones to cadmium resulted in a high level of expression of c-jun mRNA and protein, as demonstrated by Northern hybridization and Western blotting. When these clones were examined immediately after their establishment, expression of c-jun was accompanied by the appearance of a mature phenotype in many clones, as measured by the reduction of nitroblue tetrazolium and by the expression of Mac-1 (CD11b), a cell surface marker on differentiated cells. Morphological changes indicative of the differentiated state were also observed by staining. These findings indicate that expression of c-jun is capable of initiating the differentiation of WEHI-3B D+ cells in the absence of an external inducer of maturation. Furthermore, the expression of c-jun led to an enhancement of the induction of the differentiation of WEHI-3B D+ cells by retinoic acid, suggesting an involvement of c-jun in the retinoic acid signal transduction pathway.