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Blood, 1 August 2001, Vol. 98, No. 3, pp. 814-822
NEOPLASIA
p53 dysfunction in B-cell chronic lymphocytic leukemia:
inactivation of ATM as an alternative to
TP53 mutation
Andrew R. Pettitt,
Paul D. Sherrington,
Grant Stewart,
John C. Cawley,
A. Malcolm R. Taylor, and
Tatjana Stankovic
From the Department of Haematology, University of
Liverpool, and the CRC Institute for Cancer Studies, University of
Birmingham, United Kingdom.
The well-established association between TP53 mutations
and adverse clinical outcome in a range of human cancers reflects the
importance of p53 protein in regulating tumor-cell growth and survival.
Although it is theoretically possible for p53 dysfunction to arise
through mechanisms that do not involve TP53 mutation, such
a phenomenon has not previously been demonstrated in a sporadic tumor.
Here, we show that p53 dysfunction in B-cell chronic lymphocytic leukemia (CLL) can occur in the absence of TP53 mutation
and that such dysfunction is associated with mutation of the gene
encoding ATM, a kinase implicated in p53 activation. Forty-three
patients with CLL were examined for p53 dysfunction, as detected by
impaired up-regulation of p53 and of the p53-dependent protein
p21CIP1/WAF1 after exposure to ionizing radiation (IR).
Thirty (70%) patients had normal p53 responses and underwent
progressive IR-induced apoptosis. In 13 (30%) patients, p21
up-regulation was markedly impaired, indicating p53 dysfunction. Six
(14%) of these patients with p53 dysfunction had increased baseline
levels of p53, were found to have TP53 mutations, and were
completely resistant to IR-induced apoptosis. In the other 7 (16%)
patients with p53 dysfunction, IR-induced p53 up-regulation and
apoptosis were markedly impaired, but baseline levels of p53 were not
increased, and no TP53 mutations were detected. Each of
these patients was found to have at least one ATM mutation,
and a variable reduction in ATM protein was detected in all 4 patients
examined. This is the first study to provide a direct demonstration
that p53 dysfunction can arise in a sporadic tumor by a mechanism that
does not involve TP53 mutation.
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