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Blood, 15 February 2002, Vol. 99, No. 4, pp. 1411-1418
NEOPLASIA
p14ARF nuclear overexpression in aggressive B-cell
lymphomas is a sensor of malfunction of the common tumor
suppressor pathways
Abel Sánchez-Aguilera,
Margarita Sánchez-Beato,
Juan F. García,
Ignacio Prieto,
Marina Pollan, and
Miguel A. Piris
From the Molecular Pathology Program, Centro Nacional
de Investigaciones Oncológicas Carlos III (CNIO); Department of
Immunology and Oncology, CNB/CSIC-Pharmacia; Cancer Epidemiology
Service, Centro Nacional de Epidemiología, Instituto de Salud
Carlos III, Madrid, Spain.
p14ARF, the alternative product from the human
INK4a/ARF locus, antagonizes Hdm2 and mediates p53
activation in response to oncogenic stimuli. An immunohistochemical
study of p14ARF expression in 74 samples of aggressive
B-cell lymphomas was performed, demonstrating an array of different
abnormalities. A distinct nucleolar expression pattern was detected in
nontumoral tissue and a subset of lymphomas (50/74). In contrast, a
group of cases (8/74) showed absence of p14ARF expression,
dependent either on promoter hypermethylation or gene loss.
Additionally, 16 out of 74 cases displayed an abnormal nuclear
p14ARF overexpression not confined to the nucleoli, as
confirmed by confocal microscopy, and that was associated with high
levels of p53 and Hdm2. A genetic study of these cases failed to show any alteration in the p14ARF gene, but revealed the
presence of p53 mutations in over 50% of these cases. An increased
growth fraction and a more aggressive clinical course, with a shortened
survival time, also characterized the group of tumors with
p14ARF nuclear overexpression. Moreover, this
p14ARF expression pattern was more frequent in tumors
displaying accumulated alterations in the p53, p16INK4a,
and p27KIP1 tumor supressors. These observations, together
with the consideration of the central role of p14ARF in
cell cycle control, suggest that p14ARF abnormal nuclear
overexpression is a sensor of malfunction of the major cell cycle
regulatory pathways, and consequently a marker of a high tumor aggressivity.
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