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Eur J Cancer. 2013 Jan;49(1):175-84. doi: 10.1016/j.ejca.2012.07.013. Epub 2012 Aug 23.

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

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  • 1Department of Pediatric Oncology/Hematology, Erasmus Medical Center - Sophia Children's Hospital, Room: Ee15-14a, Dr. Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands.

Abstract

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.

Copyright © 2012 Elsevier Ltd. All rights reserved.

PMID:
22921182
[PubMed - indexed for MEDLINE]
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