ALL Genomes Marked by High DNA Methylation Levels

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and consists of multiple subtypes with distinct gene expression profiles defined by constellations of somatic mutations, chromosomal rearrangements deregulating oncogenes or encoding chimeric fusion transcripts and aneuploidy.

DNA methylation is tightly regulated. during development and is stably maintained in healthy cells. In contrast, cancer cells are commonly characterized by a global loss of DNA methylation co-occurring with CpG island hypermethylation. In ALL, the commonest childhood cancer, perturbations of CpG methylation have been reported.

A large team of medical scientists led by the Max Planck Institute for Molecular Genetics (Berlin, Germany) obtained diagnosis leukemia samples from children treated in St. Jude Children’s Research Hospital (Memphis, TN, USA). They performed whole-genome bisulfite sequencing across ALL subtypes, leukemia cell lines and healthy hematopoietic cells, and show that unlike most cancers, ALL samples exhibit CpG island hypermethylation, but minimal global loss of methylation.

Whole-genome, transcriptome and exome sequencing was performed using Illumina exome baits and library preparation and Illumina Hi-Seq or NovaSeq sequencers (Illumina, San Diego, CA, USA). Whole-genome bisulfite sequencing (WGBS) of primary patient samples and all cell lines except Jurkat and DND41 was performed on a bisulfite-modified DNA-sequencing library generated by the Illumina TruSeq DNA Methylation kit.

The team reported that T-ALL exhibited a global DNA methylation landscape comparable to precursor T cells derived from healthy infant thymi, whereas B-ALL samples showed mild loss of methylation at varying degrees. ALL samples exhibit CpG island hypermethylation, but minimal global loss of methylation. This was most pronounced in T cell ALL and accompanied by an exceptionally broad range of hypermethylation of CpG islands between patients, which are influenced by TET2 and DNMT3B.

The authors concluded that their study provides important data and insights into the non-canonical epigenetic regulation of ALL as well as cancer more generally that, combined with recent studies, helps to focus attention on particular aspects of the cancer methylome and will help move toward an improved mechanistic understanding of the common epigenetic changes in cancer. The study was published on May 19, 2022 in the journal Nature Cancer.

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