Researchers have announced the creation of new ‘maps’ outlining the differences between subtypes of paediatric acute lymphoblastic leukaemia (ALL).
Dr Daniel Savic of St Jude Children’s Research Hospital, Tennessee, USA, and colleagues were able to tell subtypes apart based on differences in the behaviour of chromatin: a mixture of DNA and protein that packages DNA into units within a cell nucleus.
B cell ALL is composed of diverse molecular subtypes, and survival outcomes vary considerably between these. Profiling these subtypes using transcriptional and DNA methylation has been explored in the past, but “the chromatin landscape is not well characterised for many subtypes”, the authors say.
Dr Savic said: “We wanted to understand how acute lymphoblastic leukaemia subtypes differ from one another at the genomic level and answer the question, what makes a leukemic cell a leukemic cell and not a healthy cell?
“To do this, we mapped the activity of the non-coding molecular switches that control gene expression and contribute to the formation of gene regulatory networks in patient tumour cells and compared them to healthy cells.”
In samples from 156 patients from across the US, the team assessed the whole genome for chromatin accessibility – whether the chromatin was open, allowing genes to be activated, or closed, preventing genes from being expressed.
They also looked at the presence of transcription factors – proteins which control gene expression when the chromatin is open – as well as genetic variations which may influence chromatin accessibility. In doing so, they were able to describe different subtypes of ALL by patterns of chromatin accessibility.
“Our data suggest that distinct chromatin architectures are driven by diverse transcription factors and inherited genetic variants that promote unique gene-regulatory networks,” the team conclude, in the journal Cell Genomics.
“This resource could be used to identify the underlying gene regulatory differences playing a role in treatment responses,” Dr Savic added. “By taking into account these alterations to gene regulatory networks, in the future, we could theoretically modify or generate therapeutics to treat each subtype more effectively.”
Barnett KR, Mobley RJ, Diedrich JD, Bergeron BP, Bhattarai KR, Monovich AC, Narina S, Yang W, Crews KR, Manring CS, Jabbour E, Paietta E, Litzow MR, Kornblau SM, Stock W, Inaba H, Jeha S, Pui CH, Mullighan CG, Relling MV, Pruett-Miller SM, Ryan RJH, Yang JJ, Evans WE, Savic D. (2023) “Epigenomic mapping reveals distinct B cell acute lymphoblastic leukemia chromatin architectures and regulators.” Cell Genomics, doi: 10.1016/j.xgen.2023.100442
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