Blood, Vol. 92 No. 3 (August 1), 1998:
pp. 959-967
MDM2 Protein Overexpression Inhibits Apoptosis of TF-1
Granulocyte-Macrophage Colony-Stimulating Factor-Dependent Acute
Myeloblastic Leukemia Cells
Mitsuyoshi Urashima,
Gerrard Teoh,
Dharminder Chauhan,
Atsushi Ogata,
Shuya Shirahama,
Chiharu Kaihara,
Masaharu Matsuzaki,
Hiroshi Matsushima,
Masaharu Akiyama,
Youki Yuza,
Kihei Maekawa, and
Kenneth C. Anderson
From the Department of Pediatrics, Jikei University School of
Medicine, Tokyo, Japan; Center for Hematologic Oncology, Dana-Farber
Cancer Institute and Department of Medicine, Harvard Medical School,
Boston, MA; and SRL, Inc, Tokyo, Japan.
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.
