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High incidence of potential p53 inactivation in poor outcome childhood
acute lymphoblastic leukemia at diagnosis
DI Marks, BW Kurz, MP Link, E Ng, JJ Shuster, SJ Lauer, I Brodsky and DS Haines
Department of Medicine, Medical College of Pennsylvania, Philadelphia
19102, USA.
Previous studies have indicated that p53 gene mutations were an uncommon
event in acute lymphoblastic leukemia (ALL) in children. In one series of
330 patients, p53 mutations were seen in fewer than 3%. We analyzed bone
marrow mononuclear cells derived from 10 children with ALL at diagnosis who
subsequently failed to achieve a complete remission or who developed
relapse within 6 months of attaining complete remission for p53 gene
mutations and mdm-2 overexpression. We found that three children had p53
gene mutations, and four overexpressed mdm-2. Also, experiments comparing
relative levels of mdm- 2 RNA and protein in these patients demonstrated
that mdm-2 overexpression can occur at the transcriptional and
posttranscriptional level in primary leukemic cells. Although we were
unable to link Waf-1 RNA expression with p53 status in childhood ALL, our
data show potential p53 inactivation by multiple mechanisms in a large
percentage of these patients and demonstrate that these alterations can be
detected at diagnosis. Inactivation of the p53 pathway may, therefore, be
important in children with ALL who fail to respond to treatment and may be
useful for the early identification of children requiring alternative
therapies.
Volume 87,
Issue 3,
pp. 1155-1161,
02/01/1996
Copyright © 1996 by The American Society of Hematology
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