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Overexpression of the MDM2 gene by childhood acute lymphoblastic leukemia
cells expressing the wild-type p53 gene
M Zhou, AM Yeager, SD Smith and HW Findley
Division of Pediatric Hematology/Oncology/Bone Marrow Transplantation,
Emory University School of Medicine, Atlanta, GA 30322.
The wild-type (wt) p53 tumor suppressor gene is commonly inactivated in
human malignancies, either by mutations or by loss of expression. An
additional proposed mechanism for inactivation of wt-p53 is amplification
of the murine double minute 2 (MDM2) gene and overexpression of the MDM2
protein, which binds to p53 and eliminates its tumor suppressor function.
To investigate a potential role for MDM2 in the inactivation of wt-p53 in
pediatric acute lymphoblastic leukemia (ALL), we examined the expression of
MDM2 and p53, as well as the occurrence of p53 mutations and possible
amplification of the MDM2 gene, in 19 pediatric ALL cell lines and one
pediatric acute myelogenous leukemia (AML) line. Although we did not find
significant amplification of the MDM2 gene in any of the leukemic lines, we
detected overexpression of MDM2 in all 10 lines that expressed wt-p53. Of
the 10 lines without overexpression of the MDM2 gene, six (including the
AML line) did not express p53, and four expressed mutant p53 with single
point mutations in exons 7 and 8. To determine whether primary leukemic
cells showed a similar correlation, we analyzed the original cryopreserved
leukemic bone marrow cells from seven patients from whom cell lines were
established. We obtained similar results from both the primary leukemic
cells and the corresponding cell lines: overexpression of MDM2 was present
in primary cells that expressed wt-p53 but not in cells that lacked
expression of wt-p53. These findings suggest an important role for MDM2 in
the pathogenesis of pediatric ALL in which leukemic cells express wt-p53.
Volume 85,
Issue 6,
pp. 1608-1614,
03/15/1995
Copyright © 1995 by The American Society of Hematology
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