GENISTEIN EXHIBITS PREFERENTIAL CYTOTOXICITY TO A LEUKEMOGENIC VARIANT BUT INDUCES DIFFERENTIATION OF A NON-LEUKEMOGENIC VARIANT OF THE MOUSE MONOCYTIC LEUKEMIA MM CELL-LINE

Mouse leukemia Mm-A and Mm-S2 cells are subclones of mouse monocytic l eukemia Mm cells, Mm-A cells having much higher leukemogenicity than M m-S2 cells. The growth-inhibitory effects of several protein kinase in hibitors on leukemogenic Mm-A and non-leukemogenic Mm-S2 cells were ex amined. Most inhibitors of protein serine/threonine kinases inhibited the growth of Mm-A and Mm-S2 cells similarly, but some protein tyrosin e kinase inhibitors exhibited differential inhibitory effects on Mm-A and Mm-S2 cells. Genistein inhibited growth of Mm-A cells more effecti vely than that of Mm-S2 cells, but another inhibitor of tyrosine kinas e, herbimycin A, preferentially inhibited growth of non-leukemogenic M m-S2 cells. Genistein induced or enhanced several differentiation mark ers of Mm-S2 cells, such as cell spreading, immunophagocytosis, nitrob lue tetrazolium (NBT) reduction and lysozyme activity in a dose-depend ent manner, but herbimycin A did not. Genistein was cytotoxic to Mm-A cells rather than inducing cell differentiation. Genistein has effects on several other cellular events as well as inhibition of tyrosine ki nases. However, it effectively inhibited protein tyrosine phosphorylat ion in Mm-A cells and its decrease of tyrosine phosphorylation was clo sely associated with its inhibition of cell growth. Thus, a genistein- sensitive tyrosine kinase(s) may play an important role in the growth and/or survival of leukemogenic Mm-A cells.