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Epigenetic inactivation of secreted Frizzled‐related proteins in acute myeloid leukaemia
Author(s) -
Jost E.,
Schmid J.,
Wilop S.,
Schubert C.,
Suzuki H.,
Herman J. G.,
Osieka R.,
Galm O.
Publication year - 2008
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2008.07242.x
Subject(s) - demethylating agent , biology , methylation , epigenetics , dna methylation , wnt signaling pathway , cancer research , frizzled , haematopoiesis , gene silencing , cpg site , microbiology and biotechnology , stem cell , myeloid , gene , genetics , gene expression
Summary The Wnt signalling pathway has a key function in stem cell maintenance and differentiation of haematopoietic progenitors. Secreted Frizzled‐related protein genes ( SFRPs ), functioning as Wnt signalling antagonists, have been found to be downregulated by promoter hypermethylation in many tumours. To analyse epigenetic dysregulation of SFRPs in acute myeloid leukaemia (AML), we examined the promoter methylation status of SFRP1 , ‐ 2 , ‐ 4 and ‐ 5 in AML cell lines by methylation‐specific polymerase chain reaction (MSP). Aberrant CpG island methylation was found for all four SFRP genes. By real‐time reverse transcription‐PCR, corresponding transcriptional silencing for SFRP1 and ‐ 2 was demonstrated and treatment of cell lines with 5‐aza ‐2 ′‐deoxycytidine resulted in re‐expression. The methylation status of the SFRP genes was analysed in 100 specimens obtained from AML patients at diagnosis. The frequencies of aberrant methylation among the patient samples were 29% for SFRP1 , 19% for SFRP2 , 0% for SFRP4 and 9% for SFRP5 . For SFRP2 , a correlation between promoter hypermethylation and transcriptional downregulation was found in primary AML samples. 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 SFRP2 promoter was an adverse risk factor for survival in CBF leukaemia.