Aberrant methylation of c-myc and c-fos protooncogenes and p53 tumor suppressor gene in myelodysplastic syndromes and acute non-lymphocytic leukemia

Purpose: Aberrant methylation, as an epigenetic phenomenon, may precede and regulate the expression of genes involved in transformation mechanisms that lead to leukemogenesis of hemopoietic cells. The genes involved mostly encode transcription factors and cell cycle specific inhibitors. The aim of this project was to study the DNA methylation pattern of c-myc, c-fos and p53 in myelodysplastic syndromes (MDS) and in acute non-lymphocytic leukemias (ANLL). Patients and methods: DNA was isolated from the monocyte cell layer harvested from bone marrow or peripheral blood samples of 44 patients suffering from MDS and ANLL. Genomic DNA was digested with methylation-specific enzymes, and was electrophoresed and hybridized with probes specift for human c-myc, c-fos and p53 genes. Results: In MDS, the c-myc gene in exons 2 and 3 was regionally hypomethylated, whereas exon 2 in ANLL was hypermethylated and exon 3 hypomethylated. The c-fos gene was hypomethylated in ANLL type 4 and presented aberrant hypomethylation in the different types of MDS. The p53 anti-oncogene appeared extensively hypomethylated in MDS. Conclusion: Aberrant DNA methylation pattern of the c-myc, c-fos and p53 tumor suppressor gene seems to be a primary event in the transformation process from myelodysplasia to acute leukemia, affecting their expression, and, consequently, altering the proliferation, differentiation or apoptosis of hemopoietic precursor cells. The p53 hypomethylation predisposes to critical mutations that enhance the transformation process of myelodysplasia to leukemia. The recognition of altered methylation of these genes in myelodysplasia may have prognostic implications and may lead to novel therapeutic modalities. © 2003 Zerbinis Medical Publications