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 receptor beta 2 (RAR beta 2) caused by aberrant promoter hypermethylation has been identified in several solid tumours. In order to evaluate the extent of RAR beta 2 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 RAR beta 2 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 RAR beta 2 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 RAR beta 2 promoter and the presence of CBF-MYH11 fusion transcripts (P < 0.01). Our data suggest that RAR beta 2 promoter methylation is frequent in AML and may co-operate with the expression of CBF-MYH11 fusion transcripts in leukaemogenesis.