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Blood, 1 April 2002, Vol. 99, No. 7, pp. 2291-2296
PLENARY PAPER
5' CpG island hypermethylation is associated with transcriptional
silencing of the p21CIP1/WAF1/SDI1 gene
and confers poor prognosis in acute lymphoblastic leukemia
Jose Roman-Gomez,
Juan
Antonio Castillejo,
Antonio Jimenez,
Maria Gracia Gonzalez,
Fernanda Moreno,
Maria del Carmen Rodriguez,
Manuel Barrios,
Juan Maldonado, and
Antonio Torres
From the Hematology Department, Reina Sofia Hospital,
Cordoba, Spain, and the Hematology Department, Carlos Haya Hospital,
Malaga, Spain.
The p21 is a downstream effector of p53/p73 and belongs to
the CIP/KIP family of cyclin-dependent kinase
inhibitors (CDKIs). It is, therefore, a potential tumor
suppressor gene and probably plays an important role in tumor
development. Moreover, reduced expression of p21 has been reported to
have prognostic value in several human malignancies. In contrast with
other CDKIs, mutational inactivation of p21 is infrequent, but gene
inactivation by an alternative mechanism seems to be the general
pathway. In this study, we analyzed the methylation status of the p21
promoter region using semiquantitative polymerase chain
reaction in 124 patients with acute lymphoblastic leukemia
(ALL). We observed p21 hypermethylation in bone marrow cells from 41%
(51 of 124) of ALL patients. Hypermethylation within promoter strongly
correlated with decreased p21 messenger RNA expression in
tumoral cells. Clinical, molecular, and laboratory features and
complete remission rate did not differ significantly between
hypermethylated and normally methylated patients. Estimated
disease-free survival (DFS) and overall survival at 7 and 9 years,
respectively, were 59% and 65% for healthy patients and 6% and 8%
for hypermethylated patients (P = .00001 and
P = .006). Multivariate analysis of potential prognostic
factors demonstrated that p21 methylation status was an independent
prognostic factor in predicting DFS (P = .0001). Our
results indicate that the p21 gene is subject to methylation regulation at the transcription level in ALL and seems to be an important factor in predicting the clinical outcome of these patients.
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