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p53 abnormalities in B-cell prolymphocytic leukemia
D Lens, PJ De Schouwer, RA Hamoudi, M Abdul-Rauf, N Farahat, E Matutes, T Crook, MJ Dyer and D Catovsky
Academic Department of Haematology and Cytogenetics, Royal Marsden
Hospital, London, UK.
B-cell prolymphocytic leukemia (B-PLL) is an aggressive disorder of mature
B cells with distinct clinical and pathologic features. To determine the
incidence of abnormalities of p53, we analyzed 19 cases of B-PLL by DNA
blot to assess loss of heterozygosity (LOH) at 17p13.3, by
immunocytochemistry to assess p53 expression, and by direct DNA sequencing
of polymerase chain reaction-amplified exons 5 to 9 of the p53 gene. LOH
was detected in 10 of 19 (53%) cases, p53 expression was detected in 8 of
17 (47%), and p53 mutations were detected in 10 of 19 (53%) cases. The
pattern of mutations was distinct from that observed in other B-cell
malignancies. Six cases exhibited missense mutations; 4 were transversions
and 2 were transitions. The G:C --> A:T transition at cathepsin G
dinucleotides commonly reported in p53 mutations in chronic lymphocytic
leukemia (CLL) and other hematologic malignancies was observed in only 1
case of B-PLL. Three cases exhibited deletions (ranging from 3 to 35 bp in
length) and one case exhibited a 2-bp insertion. In 1 case, a 27-bp
deletion resulted in the expression of a p53 protein lacking 9 amino acids
from the DNA binding region. All samples with p53 mutation showed loss of
germline p53 sequences. However, 3 of 10 showed no LOH by Southern blot,
indicating a localized deletion around the p53 locus at 17p13.1. Five of
the 10 cases with p53 mutation exhibited detectable p53 expression,
including 4 cases with p53 missense mutation and 1 case with deletion. Two
of 7 cases with no detectable mutation of p53 nevertheless overexpressed
p53. Therefore, there was no correlation between protein expression and p53
mutation in B-PLL. Our data indicate that the overall abnormalities of p53
occurred in 14 of 19 (75%) cases of B-PLL. The frequency of p53 mutation
(53%) in B-PLL is the highest reported in B-cell malignancies and may be
responsible for the frequent resistance to therapy of this disease. In
addition, the pattern of p53 mutation was different from that observed in
CLL and other hematologic malignancies and may indicate that a distinct
pathogenic mechanism operates in B-PLL.
Volume 89,
Issue 6,
pp. 2015-2023,
03/15/1997
Copyright © 1997 by The American Society of Hematology
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