Aberrant DNA methylation-induced gene inactivation is associated with the diagnosis and/or therapy of T-cell leukemias.
Aberrant hypermethylation of tumor suppressor genes is known to play an important role in the development of many tumors, and aberrant DNA hypermethylation was recently identified in hematologic malignancies, where it is thought to hold relevance in leukemogenesis. Here, we report that there are differences in the DNA methylation patterns seen in normal peripheral blood and two T-cell leukemia cell lines. We identify nine genes (CLEC4E, CR1, DBC1, EPO, HAL-DOA, IGF2, IL12B, ITGA1, and LMX1B) that are significantly hypermethylated in T-cell leukemias cell lines, and suggest that aberrant hypermethylation of these normally unmethylated genes may induce their transcriptional and expressional silencing. Furthermore, we observed that the expression levels of DNMT1 and DNMT3a were significantly decreased by 5-aza-2'-deoxycytidine (5-Aza-dC), which is a demethylation agent known to deplete DNA methyltransferases (DNMTs) in leukemia cancer cells and restore the expression levels of their target genes in Jurkat cells. This result suggests that the overexpression of DNMTs could contribute to the development of T-cell leukemias by inducing hypermethylation of the target genes. Together, our results show that aberrant hypermethylation is an important molecular mechanism in the progression of T-cell leukemias, and thus could prove useful as a prognostic and/or diagnostic marker. Moreover, 5-Aza-dC might be a promising candidate for the treatment of T-cell leukemia.
Division of Radiation Effect, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea.
Sun Young
SY
Kim
Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Korea.
Dong-Yeop
DY
Shin
Health Services Management, KH School of Management, Kyung Hee University, Seoul 02453, Korea.
Sang-Man
SM
Kim
Division of Radiation Effect, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea. Electronic address: mylee@kirams.re.kr.
Minyoung
M
Lee
Division of Radiation Effect, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea; Health Services Management, KH School of Management, Kyung Hee University, Seoul 02453, Korea. Electronic address: ejkim@kirams.re.kr.
Eun Ju
EJ
Kim
D000328:Adult; D001773:Blood Cells; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D015458:Leukemia, T-Cell / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D008297:Male
C000717967:DNMT3A protein, human; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C000619380:DNMT1 protein, human
5-aza-2′-deoxycytidine; Biomarkers; DNA methylation; DNA methyltransferases; Pyrosequencing; T-cell leukemia cell