MDM2 Protein Overexpression Inhibits Apoptosis of TF-1 Granulocyte-Macrophage Colony-Stimulating Factor–Dependent Acute Myeloblastic Leukemia Cells

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a growth factor for acute myeloblastic leukemia (AML) cells. Murine double minute 2 (MDM2) oncoprotein, a potent inhibitor of wild-type p53 (wtp53), can function both to induce cell proliferation and enhance cell survival, 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 both wtp53 and mutant p53 genes, showed GM-CSF–dependent growth; deprivation of GM-CSF resulted in G1 growth arrest and apoptosis. MDM2 mRNA and protein were highly expressed in proliferating TF-1 cells in the presence of GM-CSF and decreased significantly with deprivation of GM-CSF. In contrast, p53 protein increased with GM-CSF deprivation. Ectopic overexpression of MDM2 in TF-1 AML cells conferred resistance to GM-CSF deprivation, and is associated with decreased p53 protein expression. Moreover, a variant of TF-1 cells that grows in a GM-CSF–independent fashion also expressed high levels of MDM2 and low levels of p53. These results suggest that GM-CSF–independent growth of AML cells is associated with overexpression of MDM2 protein and related modulation of p53 expression.© 1998 by The American Society of Hematology.