Absence of global hypomethylation in promoter hypermethylated Mixed Lineage Leukaemia-rearranged infant acute lymphoblastic leukaemia

作者：Stumpel Dominique J P M; Schneider Pauline; van Roon Eddy H J; Pieters Rob; Stam Ronald W^*

来源：European Journal of Cancer, 2013, 49(1): 175-184.

DOI：10.1016/j.ejca.2012.07.013

• Acute lymphoblastic leukaemia
• MLL
• Infant
• Retrotransposon
• DNA methylation

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 alpha (SAT-alpha). 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.

• 出版日期2013-1