DNA methylation is one of the major epigenetic changes in human cancers, leading to silencing of tumor
suppressor genes, with a pathogenetic role in tumor development and progression in myelodysplastic
syndromes (MDS) and acute myeloid leukemia (AML). Methylation of key promoter regions, induced by
cytotoxic therapy together with complex genetic changes, is important in the biology of therapy-related
myeloid neoplasms (t-MN).
We were interested in the characterization of the methylation pattern of AML and MDS de novo and therapyrelated.
We studied 385 patients (179 females, 206 males), of a median age of 66 years (range 16-98 years).
There were 105 MDS, 208 de novo AML and 72 t-MN (45 MDS and 27 AML). Using a methylation-specific
PCR, we studied the promoter methylation status of E-cadherin (CDH1), TSP1 and DAP-Kinase 1. These genes
have been shown to be involved in the malignant transformation, interfering with angiogenesis, interaction
with micro-environment, apoptosis and xenobiotic detoxification.
We found no associations between promoter hypermethylation and gender or age at the time of initial
diagnosis. In patients with MDS, there were no associations between hypermethylation and clinical
characteristics, including IPSS score, WHO classification and cytogenetics. DAPK1 was more frequently
methylated in t-MDS/AML when compared to de novo MDS and AML (39% vs 15.3% and 24.4%, p=0.0001),
while methylation of CDH1 was similar in t-MDS/AML and AML (51% and 53.4%), but less frequent in de
novo MDS (29%) (p=0.003).
In the t-MDS/AML group, we found that the methylation pattern appeared to be related to the primary tumor,
with DAPK1 more frequently methylated in patients with a previous lymphoproliferative disease (75% vs 32%,
p=0.006). On the other hand, methylation of CDH1 was associated to radiotherapy for the primary
malignancy (84.5% vs 38%, p=0.003). TSP1 hypermethylation was rare and not characteristic of t-MDS/AML.
In 177 patients studied for concurrent methylation of several promoters, t-MN and AML de novo were
significantly more frequently hypermethylated in 2 or more promoter regions than de novo MDS (20% vs
Chemotherapy and individual genetic predisposition have a role in t-MDS/AML development, the
identification of specific epigenetic modifications may explain complexity and genomic instability of these
diseases and give the basis for targeted-therapy. The significant association with previous malignancy
subtypes may underlie a likely susceptibility to methylation of specific targets and a role for constitutional
epimutations as predisposing factors for the development of therapy-related myeloid neoplasm.