European journal of cancer (Oxford, England : 1990) · 2012
Absence of global hypomethylation in promoter hypermethylated Mixed Lineage Leukaemia-rearranged infant acute lymphoblastic leukaemia.
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Stumpel Dominique J P M, Schneider Pauline, van Roon Eddy H J, Pieters Rob, Stam Ronald W
Аннотация
BACKGROUND: Mixed Lineage Leukaemia (MLL)-rearranged acute lymphoblastic leukaemia (ALL) in infants represents a highly aggressive type of leukaemia that is often characterised by severe promoter CpG island hypermethylation. Consequently, MLL-rearranged ALL cells respond well to demethylating cytosine analogue drugs. In human cancer cells, enhanced promoter methylation is typically accompanied by global loss of methylation in non-promoter regions of the genome. In turn, global hypomethylation usually leads to genomic instability, which may have contributed to cancer development.
DESIGN AND METHODS: Here we examined global methylation densities in MLL-rearranged infant ALL (n=45) samples in comparison with germline MLL infant ALL (n=11), non-infant B-cell precursor ALL (n=11) and normal paediatric bone marrow (n=9) samples. For this we performed high-resolution bisulfite pyrosequencing to determine methylation levels at the repetitive elements LINE-1, Alu and satellite α (SAT-α). As an additional measure of global methylation levels we used the LUminometric Methylation Assay (LUMA).
RESULTS: We found that MLL-rearranged infant ALL is not characterised by global hypomethylation, despite its characteristic promoter CpG hypermethylation patterns. Instead we observed a moderate trend towards global hypermethylation and demonstrated that these methylated non-promoter sequences are responsive to demethylating agents.
CONCLUSIONS: MLL-rearranged infant ALL cells are characterised by an overall methylated genomic state, and both promoter and non-promoter methylation responds to demethylating agents, which may further explain the remarkable sensitivity of these cells for the methylation-inhibiting therapeutics.
DESIGN AND METHODS: Here we examined global methylation densities in MLL-rearranged infant ALL (n=45) samples in comparison with germline MLL infant ALL (n=11), non-infant B-cell precursor ALL (n=11) and normal paediatric bone marrow (n=9) samples. For this we performed high-resolution bisulfite pyrosequencing to determine methylation levels at the repetitive elements LINE-1, Alu and satellite α (SAT-α). As an additional measure of global methylation levels we used the LUminometric Methylation Assay (LUMA).
RESULTS: We found that MLL-rearranged infant ALL is not characterised by global hypomethylation, despite its characteristic promoter CpG hypermethylation patterns. Instead we observed a moderate trend towards global hypermethylation and demonstrated that these methylated non-promoter sequences are responsive to demethylating agents.
CONCLUSIONS: MLL-rearranged infant ALL cells are characterised by an overall methylated genomic state, and both promoter and non-promoter methylation responds to demethylating agents, which may further explain the remarkable sensitivity of these cells for the methylation-inhibiting therapeutics.