5' CpG island hypermethylation is associated with transcriptional silencing of the p21(CIP1/WAF1/SDI1) gene and confers poor prognosis in acute lymphoblastic leukemia.
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.
Roman-Gomez
Jose
J
Hematology Department, Reina Sofia Hospital, Avda. Menendez Pidal s/n, 14004 Cordoba, Spain. peperosa@teleline.es
Castillejo
Juan Antonio
JA
Jimenez
Antonio
A
Gonzalez
Maria Gracia
MG
Moreno
Fernanda
F
Rodriguez
Maria del Carmen
Mdel C
Barrios
Manuel
M
Maldonado
Juan
J
Torres
Antonio
A
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D019175:DNA Methylation; D015226:Dinucleoside Phosphates / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D007223:Infant; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D015183:Restriction Mapping; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D013997:Time Factors; D014158:Transcription, Genetic
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D015226:Dinucleoside Phosphates; D004791:Enzyme Inhibitors; C493956:CDKN1A protein, human; C015772:CpG dinucleotide