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 leukemia Mm cells, Mm-A cells having much higher leukemogenicity than Mm-S2 cells. The growth-inhibitory effects of several protein kinase inhibitors on leukemogenic Mm-A and non-leukemogenic Mm-S2 cells were examined. Most inhibitors of protein serine/threonine kinases inhibited the growth of Mm-A and Mm-S2 cells similarly, but some protein tyrosine kinase inhibitors exhibited differential inhibitory effects on Mm-A and Mm-S2 cells. Genistein inhibited growth of Mm-A cells more effectively than that of Mm-S2 cells, but another inhibitor of tyrosine kinase, herbimycin A, preferentially inhibited growth of non-leukemogenic Mm-S2 cells. Genistein induced or enhanced several differentiation markers of Mm-S2 cells, such as cell spreading, immunophagocytosis, nitroblue tetrazolium (NBT) reduction and lysozyme activity in a dose-dependent 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 kinases. However, it effectively inhibited protein tyrosine phosphorylation in Mm-A cells and its decrease of tyrosine phosphorylation was closely 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.