Publikationsserver der RWTH Aachen University
Zur epigenetischen Inaktivierung der Wnt-Antagonisten SFRP-1, -2, -4 und -5 bei der Akuten Myeloischen Leukämie
Abstract
dc:descriptionAcute myeloid leukaemia (AML) originates in the transformation of hematopoietic stem cells, leading to clonal proliferation of immature progenitor cells and severe multilineage bone marrow suppression. In addition to numerous genetic aberrations in AML, it has become evident that epigenetic alterations play a significant role in the pathogenesis of AML. Silencing of tumor suppressor gene expression by aberrant CpG methylation in promoter regions is an established epigenetic principle in carcinogenesis. The Wnt signaling pathway plays a key role in cell proliferation as well as differentiation and has been shown to be important for normal hematopoiesis. The family of secreted Frizzled-related proteins (SFRPs), functioning as Wnt signaling antagonists, has been found to be downregulated by promoter hypermethylation in acute lymphoblastic leukaemia (ALL) and solid tumors. Data suggest a correlation between epigenetic silencing of SFRPs and poor prognosis in ALL. To demonstrate the relevance of SFRP downregulation in AML, we examined the promoter-associated methylation status of CpG islands of SFRP-1,-2,-4 and -5 in the AML cell lines KG1a and HL60 and the Burkitt’s lymphoma cell line Raji by methylation-specific polymerase chain reaction (MSP). Promoter hypermethylation was found for all four SFRP genes in HL60 and Raji and for SFRP-1,-2 and -5 in KG1a. Transcriptional gene silencing as a consequence of SFRP hypermethylation was confirmed by real-time reverse transcriptase quantitative polymerase chain reaction (RT-PCR) for SFRP-1 and SFRP-2 in both AML cell lines. Treatment of KG1a and HL60 with the demethylating agent 5-aza-2’deoxycytidine led to a reexpression of SFRP-1 and SFRP-2 in real-time RT-PCR analysis. By MSP, we analyzed the methylation status of SFRP-1,-2,-4 and -5 in 97 specimens obtained from AML patients at diagnosis. The frequencies of aberrant methylation among the primary patient samples were 28,9% (28/97) for SFRP-1, 18,6% (18/97) for SFRP-2, 0% (0/97) for SFRP-4 and 8,2% (8/97) for SFRP-5. Among AML cases with a favourable karyotype, hypermethylation of SFRP genes was restricted to patients with core binding factor (CBF) leukaemia and aberrant methylation of the SFRP-2 promoter was an adverse risk factor for survival in CBF leukaemia. Our results indicate that hypermethylation of the SFRP promoter region is a frequent epigenetic event in AML, with the potential to cause aberrant Wnt signaling. The role of SFRP promoter hypermethylation as a prognostic biomarker in AML needs to be further assessed in large prospective trials.
Degree
thesis:*- Grantor dc:publisher
- Publikationsserver der RWTH Aachen University
- Year dc:date
- 2010
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Schmid, Julia
- Contributors dc:contributor
-
- Osieka, Rainhardt
Subjects
dc:subject × 7Rights
dc:rights- Statement dc:rights
-
- info:eu-repo/semantics/openAccess
- Language dc:language
- ger