Various haematopoietic malignancies are known to be driven by somatic chromosomal translocations, whereby oncogenes near the fusion junction become activated. Burman et al. collated a list of 74 genes that are known to be recurrently affected by translocations in clinical samples of haematopoietic malignancies, as well as 100 negative-control genes per translocation-prone gene. To identify chromatin features that correlate with translocation propensity, they mined data from the US National Institutes of Health (NIH) Roadmap Epigenomics Project, comprising genome-wide maps of various histone modifications and DNaseI-based chromatin accessibility in normal CD34+ haematopoietic cells. This cell type was chosen as it is thought to be where the cancer-associated translocations initially occur. The investigators found that various marks of open chromatin — including enrichment for histone H3 monomethylated on lysine 4 (H3K4me1) and depletion of H3K9me3 — were found in the translocation-prone genes. Importantly, although transcriptional activation has been previously associated with these open chromatin marks and with translocation propensity, there was no difference in overall transcriptional activity between the set of translocation-prone genes and the negative-control genes, indicating that the chromatin state might influence translocation occurrences independently from its role in transcriptional activation.
To test the correlation between chromatin state and translocations within the same cell lines, the authors examined two anaplastic large cell lymphoma (ALCL) cell lines that are known to be prone to a chromosomal translocation between the nucleophosmin 1 (NPM1) and anaplastic lymphoma kinase (ALK) genes following γ-irradiation-induced DNA breaks. Compared with non-translocation-prone cell lines, the ALCL cell lines showed H3K4me1 enrichment and H3K9me3 depletion at the NPM1 and ALK loci, despite no measurable difference in transcriptional activity at each locus between these cell types.
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