30 March 2020

Scientists have found previously undiscovered structural changes in the DNA of T cell acute lymphoblastic leukaemia (T-ALL) cells.

A team led by Prof Iannis Aifantis and Dr Aristotelis Tsirigos from NYU Grossman School of Medicine in New York, USA, examined structural changes in the layout of chromosomes and how they differ between T-ALL subtypes and normal T-cells.

Inside the cell nucleus, DNA chains exist in organised chromosome groupings called topographically associated domains, or TADs. The activity of genes in each domain can be dialled up or down by sections of DNA called enhancers. But the team found that in this form of leukaemia, the boundaries between different TADs change. These means that parts of DNA can interact with enhancers from the wrong domains. Consequently, this can increase the action of certain genes and encourage cancer growth and spread, according to the researchers.

The team believes this mechanism could be equally as important as gene mutations.

Dr Palaniraja Thandapani, co-first author on the study, says: “Our study is the first to show that the naturally ‘looped’ structure of genetic material in blood cells is changing in T cell leukaemia. With this in mind, the most effective treatment for this type of leukaemia may be a combination of a drug that targets the disease's cancer-causing, genetic mutations and another that counters any changes to chromosomal 3D structure.”

Findings were published in Nature Genetics. Dr Aristotelis Tsirigos adds that these changes in DNA looping were unique to the T cell leukaemia they were studying, and that looping alterations may be different in other cancers.

“Once these 3D genetic changes are fully described, we should be able to test existing and new drugs based on their ability to correct any malformations and better predict the chances for patient survival from cancer,” he says.

Source: Kloetgen A, Thandapani P, Ntziachristos P, Ghebrechristos Y, Nomikou S, Lazaris C, Chen X, Hu H, Bakogianni S, Wang J, Fu Y, Boccalatte F, Zhong H, Paietta E, Trimarchi T, Zhu Y, Van Vlierberghe P, Inghirami GG, Lionnet T, Aifantis I, Tsirigos A. (2020) “Three-dimensional chromatin landscapes in T cell acute lymphoblastic leukemia”, Nature Genetics, doi: 10.1038/s41588-020-0602-9


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