Aberrante DNA-Methylierung des Transkriptionsfaktors C/EBP[alpha] bei akuter myeloischer Leukämie

Abstract

Based on the role of epigenetic changes as an alternative mechansim of transcriptional inactivation of cancer-related genes in hematopoietic malignancies as well as the relevance of CCAAT/enhancer binding protein alpha (C/EBP alpha) in early stages of myeloid differentiation and regulation we investigated the methylation status of the C/EBP alpha promotor region near the transcription start site in acute myelogenous leukemia (AML). Aberrant methylation of the C/EBP alpha promotor region was found in 10/80 (12,5%) primary samples from AML in the French-American-British (FAB)-subtypes M1, M2, M4, M4eo und M5. Moreover hypermethylation was detected exclusively in cytogenetically favorable and intermediate risk groups. Clinical trials with demethylating agents as 5-aza-2’-desoxycytidine (DAC) und 5-azacytidin (AZA) provided promising findings in therapy of acute leukemias and myelodysplastic syndrome (MDS). We showed, that in hematopoietic tumor cell lines, CpG island hypermethylation of the proximal C/EBP alpha promotor region was associated with transcriptional silencing, and treatment with the demethylating agent DAC resulted in C/EBP alpha reexpression and promotor demethylation. C/EBP alpha has been shown to regulate cell cycle progression through inhibition of cyclin-dependent-kinase (CDK) 2 and 4. Therefore we investigated a possible relationship between the methylation patterns of C/EBP alpha and another cell cycle regulator p15, which is a common target for epigenetic inactivation in AML. Our data indicate an inverse correlation between aberrant methylation of C/EBP alpha and the negative cell cycle regulator p 15. This context should be evaluated in more extensive trials. The investigation of pathophysiological coherency between aberrant C/EBP alpha methylation and C/EBP alpha-mutation could be interesting concerning genetic and epigenetic mechanisms. In addition to that C/EBP alpha may add to the list of epigenetically silenced tumor suppressor genes with a well-defined biological role in leukemogenesis that could be used for disease stratification as well as a therapeutic target