MODULATION OF GENE-EXPRESSION IN THE ACUTE PROMYELOCYTIC LEUKEMIA-CELL LINE NB4

The human leukemic cell line NB4 was derived from a patient with acute promyelocytic leukemia and is characterized by a specific 15;17 chrom osomal translocation. We analyzed the response of NB4 and HL-60 cells to the biomodulators all-trans-retinoic acid (ATRA), vitamin D3 (Vit D 3) and the protein kinase C agonists bryostatin 1 (Bryo 1) and phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA). HL-60 cells were us ed for comparison being arrested at the myeloblastic-promyelocytic sta ge, but lacking the t(15;17) abnormality. In most experiments Vit D3 w as only weakly or not at all effective. The other three reagents effec tively slowed or stopped the proliferation of the cells in suspension. Associated with this proliferation arrest was the cell differentiatio n along the myeloid cell lineages: ATRA modulated morphological featur es indicative of granulocytic differentiation; Bryo 1 and TPA caused a lso distinct morphological changes. The inducers up-regulated the expr ession of CD11b (without changing the surface expression of other mark ers, e.g. CD13, CD14, CD15, CD33, CD68, HLA-DR) and completely down-re gulated the originally strong expression of myeloperoxidase and c-myc at the mRNA level. Thus, ATRA- or protein kinase C activator-induced d ifferentiation involved changes associated with maturational processes . Induction of terminal differentiation of leukemic cells by physiolog ical or pharmacological modulators may be able to control the growth o f the malignant cells and has therapeutic implications.