MDM2 PROTEIN OVEREXPRESSION INHIBITS APOPTOSIS OF TF-1 GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR-DEPENDENT ACUTE MYELOBLASTIC-LEUKEMIA CELLS

Granulocyte-macrophage colony-stimulating factor (GMCSF) is a growth f actor for acute myeloblastic leukemia (AML) cells. Murine double minut e 2 (MDM2) oncoprotein, a potent inhibitor of wild-type p53 (wtp53), c an function both to induce cell proliferation and enhance cell surviva l, and is frequently overexpressed in leukemias. Therefore, we focused on the importance of MDM2 protein in GM-CSF-dependent versus GM-CSF- independent growth of AML cells. The TF-1 AML cell line, which has bot h wtp53 and mutant p53 genes, showed GM-CSF-dependent growth; deprivat ion of GM-CSF resulted in G1 growth arrest and apoptosis, MDM2 mRNA an d protein were highly expressed ire proliferating TF-1 cells in the pr esence of GM-CSF and decreased significantly with deprivation of GM-CS F. In contrast, p53 protein increased with GM-CSF deprivation, Ectopic overexpression of MDM2 in TF-1 AML cells conferred resistance to GM-C SF deprivation, and is associated with decreased p53 protein expressio n. Moreover, a variant of TF-1 cells that grows in a GM-CSF-independen t fashion also expressed high levels of MDM2 and low levels of p53, Th ese results suggest that GM-CSF-independent growth of AML cells is ass ociated with overexpression of MDM2 protein and related modulation of p53 expression. (C) 1998 by The American Society of Hematology.