Study of gene promoter methylation in acute promyelocytic leukaemia
Study of Gene Promoter Methylation in Acute Promyelocytic Leukaemia
DNA methylation, catalyzed by DNA methyltransferase, involves the addition of a methyl group to the carbon 5 position of the cytosine ring in the CpG dinucleotide and results in the generation of methylcytosine.
In cancer, aberrant methylation of specific gene
silencing, and serves as an alternative mechanism of gene inactivation.
Apart from cellular oncogenes,
an important event and CDKN2B (P15INK4B)
carcinogenesis. CDKN2A (p16INK4A)
two closely linked tumor suppressor genes located at
encoding for p16 and p15 cyclin-
dependent kinase inhibitors.
While most tumor suppressor genes such as Rb and p53 are inactivated by point mutation in one allele and deletion of the other, the major mechanism of p15 gene inactivation in AML is through aberrant methylation of the 5' promoter region.
characterized by t(15;17) with generation of a chimeric
PML/ RARa gene responsible for leukemogenesis. Recently, all-trans retinoic acid (ATRA) and arsenic trioxide have been shown to induce differentiation and apoptosis of the neoplastic promyelocytes.
Studies were performed to test the hypotheses:
1. p15 and p16 are frequently methylated in APL
Diagnostic bone marrow DNA from 26 APL patients was
reaction (MSP) with primers for methylated (M-MSP) and
methylation, whereas only three patients (11.5%) showed
p16 methylation, methylation.
of who had concomitant p15
2. Adverse prognostic impact of p15 methylation on APL
Disease-free (DFS) and overall (OS) survivals were correlated with p15 methylation status at diagnosis. The five-year DFS of patients with p15 methylation was significantly inferior to those without (15% versus
62.5%, p multivariate
0.02); and this remained significant in
morphologic subtypes, and presenting leukocyte counts in addition to p15 methylation status.
3. p15 methylation serves as a disease marker of MRD
MSP for sensitivity of
p15 gene 10-5?Six
methylation has a
patients with serial
samples during the course of disease were evaluated with MSP for p15 methylation at diagnosis and follow-up.
hematological negative MSP
for p15 methylation
prolonged survival in another four patients.
4. Multiple genes are methylated in addition to p15 and p16
The methylation status of a panel of nine genes including p15, p16, p73, VHL, E-CAD, Caspase 8, MGMT,
RAR~, and estrogen receptor (ER) was analyzed by MSP in the diagnostic bone marrow samples of 23 APL patients. Methylation of p15, RAR~, ER and p16 was detected in 17
(73.9%) , 10 (43.4%) , 5 (21.7%) and 3 (13%) patients at
diagnosis but not in p73, VHL, E-CAD, caspase 8 and MGMT.
In conclusion, preferential methylation of selected genes (such as P15, ER and RARf3) occurs in APL. p15 methylation might be of prognostic significance, and is a potential marker of MRD in APL.
School:The University of Hong Kong
School Location:China - Hong Kong SAR
Source Type:Master's Thesis
Keywords:methylation acute myelocytic leukemia genetic aspects
Date of Publication:01/01/2002