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Promoter hypermethylation of the retinoic acid receptor β2 gene is frequent in acute myeloid leukaemia and associated with the presence of CBFβ–MYH11 fusion transcripts

Silencing of the putative tumour suppressor gene retinoic acid receptorβ2 (RARβ2) caused by aberrant promoter hypermethylation has been identified in several solid tumours. In order to evaluate the extent of RARβ2 hypermethylation and transcription in acute myeloid leukaemia (AML) at diagnosis, 320 patients were investigated by bisulphite‐denaturing gradient gel electrophoresis and mRNA transcription levels were analysed in 61 of these by quantitative real‐time polymerase chain reaction. The results were compared with demographic‐ and molecular data from the patients. While RARβ2 was unmethylated in 10/10 bone marrow and 7/7 blood samples from healthy individuals, the gene was hypermethylated in 43% of the AML patients. The RARβ2 degree of promoter methylation differed between and within individuals, and the mRNA transcription levels of the gene varied inter‐individually by a factor of 4000. A significant inverse correlation between promoter hypermethylation and gene expression could be established (t‐test, P = 0·019). Comparison of methylation data with a series of other molecular alterations in the same patient materials revealed a correlation between hypermethylation of the RARβ2 promoter and the presence of CBF‐MYH11 fusion transcripts (P < 0·01). Our data suggest that RARβ2 promoter methylation is frequent in AML and may co‐operate with the expression of CBF‐MYH11 fusion transcripts in leukaemogenesis.