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Nonhereditary p53 mutations in T-cell acute lymphoblastic leukemia are
associated with the relapse phase
MH Hsiao, AL Yu, J Yeargin, D Ku and M Haas
Department of Biology/Cancer Center, University of California, San Diego,
La Jolla 92093-0063.
We have previously reported that greater than 60% of human leukemic T- cell
lines possess mutations in the p53 tumor suppressor gene. To determine
whether T-cell acute lymphoblastic leukemia (T-ALL) patient samples possess
p53 mutations, we screened peripheral blood-and bone marrow-derived
leukemia samples, taken at diagnosis and at relapse, for p53 mutations.
Exons 4 through 9 and selected intron regions of the p53 gene were analyzed
using polymerase chain reaction-single-strand conformation polymorphism and
direct sequencing. p53 mutations were found in 0 of 15 T-ALL diagnosis
samples, as compared with 10 of 36 (28%) T-ALL relapse samples. To
determine whether p53 mutations play a role in the recurrence (relapse) of
T-ALL, two special groups of T-ALL patients were studied: (1) a group of 8
relapse patients whose disease was refractory to chemotherapeutic
treatment, and (2) a group of 6 "paired" T-ALL cell samples from patients
for whom we possess both diagnosis and relapse samples. Three of 8 relapsed
patients (37.5%) whose disease was refractory to the reinduction of
remission by chemotherapy possessed missense mutations of the p53 gene. All
3 cases had mutations in exon 5. Among the paired samples, 3 of 6 patients
harbored p53 mutations at disease recurrence, but possessed only wild- type
p53 alleles at diagnosis. One case had mutation on exon 4, 1 case in exon
5, and 1 case in exon 8 with loss of heterozygosity. These data clearly
indicate that recurrence of T-ALL is associated with missense mutations in
p53. Our results indicate that (1) mutations of p53 do occur in T-ALL in
vivo, and such mutations are associated with the relapse phase of the
disease; and (2) p53 mutation is involved in the progression of T-ALL. This
conclusion is supported by our observation that the introduction of
T-ALL-derived mutant p53 expression constructs into T-ALL cell lines
further increases their growth rate in culture, enhances cell cloning in
methylcellulose, and increases tumor formation in nude mice.
Volume 83,
Issue 10,
pp. 2922-2930,
05/15/1994
Copyright © 1994 by The American Society of Hematology
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