Childhood acute lymphoblastic leukaemia (ALL) is a disease that originates before birth from the proliferation of neoplastic lymphoid precursor cells in the bone marrow. Previously, we identified dense, biallelic methylation of the TES promoter as the most common molecular event in ALL being present in over 90% of B-ALL and 70% of T-ALL cases. We developed an array-based CpG region analysis pipeline (ABC.RAP) R package to analyse human DNA methylation array datasets. Exploring publicly available datasets, we found about 200 genes that are differentially methylated in ALL. The large number and consistency of the epigenetically modified genes raise the possibility that methylation-induced gene silencing in ALL may not be an acquired cancer-related phenomenon. We propose the presence of a distinct population of normal fetal lymphocytes that carry an epigenetic profile similar to that of ALL.
We developed an assay to detect methylated TES alleles using a deep targeted sequencing approach (MiSeq; Illumina). To date, we have examined blood samples from four neonates, and 10 cord blood samples. Remarkably, we detected the ALL-like methylation profile, i.e., TES methylated alleles, in one of the premature babies (3.2% of the CD19+ B cells of a four week-old, 28 week-gestation baby), and in three of 10 sequenced cord blood samples (1.3%, 0.16%, and 1.2% of CD19 negative cells). Importantly, methylation of TES has never been observed in normal adult blood. The next stage is to search for enrichment of the methylated TES alleles in purified stem cells, T cells and B cells.