Untersuchungen zum Methylierungsstatus von TLE1 bei der akuten myeloischen Leukämie

Tumorigenesis is regarded as a multistep process involving genetic alterations and epigenetic modifications changing gene expression. There is increasing evidence for epigenetic alterations, such as hypermethylation of CpG islands near promoter regions, playing an important role in carcinogenesis. Acute myeloid leukemia (AML) is a heterogeneous disease characterized by clonal proliferation of hematopoietic progenitor cells. In AML epigenetic silencing of tumor suppressor genes has been shown to maintain the development of a malignant phenotype. The Groucho/Transducin-like Enhancer of split (TLE) family proteins are transcriptional corepressors, regulating cell proliferation and differentiation. TLE1 is regarded as a putative tumor suppressor gene that may be involved in the pathogenesis of hematopoietic malignancies. Several studies have implicated the loss of TLE1 expression in the pathogenesis of hematopoietic malignancies, including AML. In this study, we assessed the methylation status of promoter-associated CpG islands of TLE1 in AML cell lines and patient samples, analyzing the frequency of DNA hypermethylation in AML. We first analyzed the methylation status of TLE1 promoter region by methylation-specific polymerase chain reaction (MSP) in hematopoietic tumor cell lines. In AML cell lines, SET-2 was unmethylated, while HL-60, KG-1a and GDM-1 were methylated. Although we found 75% (3 of 4) AML cell lines methylated, there was no aberrant methylation in 106 patient samples. Our data indicates that TLE1 hypermethylation is not a common event in adult AML primary tissues. Although epigenetic silencing by DNA hypermethylation could not be detected in this case, disruption of TLE1 transcription by histone modification remains unclear. Due to the importance of epigenetic modifications as potential biomarkers or therapeutic targets, further studies should be performed to identify tumor-associated epigenetic profiles. In view of the increasing specification of epigenetic therapeutics, candidate gene analysis may play an important role in the development of new or improved treatment options