Abstract
BackgroundAberrant promoter DNA methylation has been reported in childhood acute lymphoblastic leukaemia (ALL) and has the potential to contribute to its onset and outcome. However, few reports demonstrate consistent, prevalent and dense promoter methylation, associated with tumour-specific gene silencing. By screening candidate genes, we have detected frequent and dense methylation of the TESTIN (TES) promoter.ResultsBisulfite sequencing showed that 100% of the ALL samples (n = 20) were methylated at the TES promoter, whereas the matched remission (n = 5), normal bone marrow (n = 6) and normal PBL (n = 5) samples were unmethylated. Expression of TES in hyperdiploid, TEL-AML+, BCR-ABL+, and E2A-PBX+ subtypes of B lineage ALL was markedly reduced compared to that in normal bone marrow progenitor cells and in B cells. In addition TES methylation and silencing was demonstrated in nine out of ten independent B ALL propagated as xenografts in NOD/SCID mice.ConclusionIn total, 93% of B ALL samples (93 of 100) demonstrated methylation with silencing or reduced expression of the TES gene. Thus, TES is the most frequently methylated and silenced gene yet reported in ALL. TES, a LIM domain-containing tumour suppressor gene and component of the focal adhesion complex, is involved in adhesion, motility, cell-to-cell interactions and cell signalling. Our data implicate TES methylation in ALL and provide additional evidence for the involvement of LIM domain proteins in leukaemogenesis.
Highlights
Aberrant promoter DNA methylation has been reported in childhood acute lymphoblastic leukaemia (ALL) and has the potential to contribute to its onset and outcome
The TES promoter was the most frequently methylated, with four out of five ALL samples showing a high percentage of methylation
ALL5 (T lineage; Age: 7 years 7 months), for which methylation was not detected by Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), showed the lowest level of methylation, but was methylated at CpG sites other than the HhaI site interrogated by MS-MLPA
Summary
Aberrant promoter DNA methylation has been reported in childhood acute lymphoblastic leukaemia (ALL) and has the potential to contribute to its onset and outcome. Few reports demonstrate consistent, prevalent and dense promoter methylation, associated with tumour-specific gene silencing. Methylation of gene promoters is a mechanism by which tumour suppressor genes can be inactivated. The role of promoter methylation in carcinogenesis has been convincingly demonstrated when gene methylation constitutes one of two events causing inactivation of welldocumented tumour suppressor genes. Distinction of genes whose methylation is causally associated with malignant transformation from those that are affected by non-specific methylation remains problematic. Promoter methylation can occur as a non-specific "bystander" event affecting genes that are already silent in non-malignant tissue. Keshet et al reported that of 106 genes whose promoters were methylated in colon cancer cell lines, 91 were already inactive in normal colon [4]. In acute lymphoblastic leukaemia (ALL), the methylated gene TIMP3 was not expressed regardless of its methylation status [5]
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