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Epigenetic changes including DNA methylation play an important role in oncogenesis in addition to genetic changes and chromosomal translocations. To clarify the changed pattern of DNA methylation in hematological malignancies, we isolated aberrantly methylated DNA regions by Methylated CpG island amplification/representative difference assay (MCA/RDA).
In ATL cells, MEL1S gene was identified as hypomethylated one in ATL cells. Aberrant expression of MEL1S gene was observed in ATL cells, which enables ATL cells resistant to TGF-β. Therefore, MEL1S expression is considered to be one of mechanisms to confer the resistance to TGF-β. On the other hand, many genes were found to be hypermethylated in ATL cells. Among them, KLF4 and EGR3 genes were studied in ATL cells. EGR3 gene is a transcriptional factor, which is critical for Fas ligand gene transcription. Although ATL cells highly express Fas antigen, they escape from apoptosis due to loss of Fas ligand expression. Silenced EGR3 gene expression in ATL cells is considered to result in loss of Fas ligand expression, which enables ATL cells to escape from Fas-Fas ligand induced apoptosis.
With MCA/RDA, we also identified hyper and hypomethylated DNA regions in B-cell chronic lymphocytic leukemia (B-CLL) compared with normal CD19 positive B-cells. We isolated 5 hyper and 27 hypomethylated DNA regions in genomic DNA from B-CLL patient. Hypomethylated DNA regions clustered in chr. 9q34,10q25-26, and 19q13.
These aberrantly methylated genes should be implicated in oncogenesis of these hematological malignancies, and detection of these methylation can be used for diagnosis and estimation of the prognosis.