title: Promoter hypermethylation of the retinoic acid receptor beta2 gene is frequent in acute myeloid leukaemia and associated with the presence of CBFbeta-MYH11 fusion transcripts.
abstract: Silencing of the putative tumour suppressor gene retinoic acid receptor beta2 (RARbeta2) caused by aberrant promoter hypermethylation has been identified in several solid tumours. In order to evaluate the extent of RARbeta2 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 RARbeta2 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 RARbeta2 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 RARbeta2 promoter and the presence of CBF-MYH11 fusion transcripts (P < 0.01). Our data suggest that RARbeta2 promoter methylation is frequent in AML and may co-operate with the expression of CBF-MYH11 fusion transcripts in leukaemogenesis.
authors.affiliation: Department of Haematology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Anita
authors.initials: A
authors.lastname: Rethmeier
authors.forename: Anni
authors.initials: A
authors.lastname: Aggerholm
authors.forename: Lene Hyldahl
authors.initials: LH
authors.lastname: Olesen
authors.forename: Caroline
authors.initials: C
authors.lastname: Juhl-Christensen
authors.forename: Charlotte Guldborg
authors.initials: CG
authors.lastname: Nyvold
authors.forename: Per
authors.initials: P
authors.lastname: Guldberg
authors.forename: Peter
authors.initials: P
authors.lastname: Hokland
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019175:DNA Methylation; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: C095514:CBFbeta-MYH11 fusion protein; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta