Methylation of tumour suppressor gene promoters in the presence and absence of transcriptional silencing in high hyperdiploid acute lymphoblastic leukaemia (2009)

Author(s): Paulsson K, An Q, Moorman AV, Parker H, Molloy G, Davies T, Griffiths MJ, Ross FM, Irving JAE, Harrison CJ, Young BD, Strefford JC

    Abstract: Promoter methylation is a common phenomenon in tumours, including haematological malignancies. In the present study, we investigated 36 cases of high hyperdiploid (>50 chromosomes) acute lymphoblastic leukaemia (ALL) with methylation-specific multiplex ligase-dependent probe amplification to determine the extent of aberrant methylation in this subgroup. The analysis, which comprised the promoters of 35 known tumour suppressor genes, showed that 16 genes displayed abnormal methylation in at least one case each. The highest number of methylated gene promoters seen in a single case was thirteen, with all but one case displaying methylation for at least one gene. The most common targets were ESR1 (29/36 cases; 81%), CADM1 (IGSF4, TSLC1; 25/36 cases; 69%), FHIT (24/36 cases; 67%) and RARB (22/36 cases; 61%). Interestingly, quantitative reverse transcription-polymerase chain reaction showed that although methylation of the CADM1 and RARB promoters resulted in the expected pattern of downregulation of the respective genes, no difference could be detected in FHIT expression between methylation-positive and -negative cases. Furthermore, TIMP3 was not expressed regardless of methylation status, showing that aberrant methylation does not always lead to gene expression changes. Taken together, our findings suggest that aberrant methylation of tumour suppressor gene promoters is a common phenomenon in high hyperdiploid ALL.

      • Date: 22-12-2008
      • Journal: British Journal of Haematology
      • Volume: 144
      • Issue: 6
      • Pages: 838-847
      • Publisher: Wiley-Blackwell Publishing Ltd.
      • Publication type: Article
      • Bibliographic status: Published

      Keywords: Adolescent Chi-Square Distribution Child Child, Preschool CpG Islands *DNA Methylation *Diploidy Female Gene Silencing *Genes, Tumor Suppressor Humans Infant Karyotyping Male Middle Aged Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics *Promoter Regions, Genetic Reverse Transcriptase Polymerase Chain Reaction/methods Sequence Analysis, DNA Transcription, Genetic


      Dr Julie Irving
      Reader in Experimental Haematology

      Professor Anthony Moorman
      Professor of Genetic Epidemiology