The most common form of childhood cancer is acute lymphoblastic leukaemia (ALL). Together with Karolinska Institutet, SciLifeLab and the University of Cambridge, researchers at Lund University have conducted the largest ever analysis of ALL at protein level by studying activity in more than 8,000 genes and proteins. The results of the study show a deviant folding of the DNA strand which in turn affects the genes’ activity. The study is now being published in Nature Communications.
Approximately a quarter of all the children who are afflicted by ALL have a form of leukaemia which is characterised by the diseased cells containing too many chromosomes. This is known as hyperdiploidy. Sometimes as many as 67 chromosomes can be found in one cell.
“In earlier studies, we have shown that the genes on the extra chromosomes control the development of leukaemia by becoming more active. This causes an imbalance in the cells which, for example, can make them divide faster,” says Kajsa Paulsson, associate professor at Lund University and the final author of the study.
However, up until now, it has not been understood exactly how this happens. Now the researchers have studied that activity in more than 8,000 genes and proteins and a study of that size has never been done before on this form of cancer.
“The advantage of studying proteins is that the information is of greater biological relevance. If you only look at RNA level and then translate it to protein level, the link is not fully clear,” Kajsa Paulsson explains.
“This is a relatively new area of research and also, it is more difficult to study this at protein level but the advantage is that this gives us a better picture of how the cell is controlled compared with if we only study the genes,” says Janne Lehtiö, professor at Karolinska Institutet and co-author of the study.
In the hyperdiploid leukaemia cases, the researchers could see that the levels of the protein CTCF and the protein complex cohesin, which control how the DNA strand in the cell is folded, were lower than in the leukaemia cases where there were no extra chromosomes. The researchers therefore investigated how DNA is folded in hyperdiploid leukaemia and they were able to see that some of the cases presented a deviant type of folding.
“The way DNA is folded is of major importance for the regulation of when genes are to be active or not. We could also see that the hyperdiploid leukaemia cases presented signs of incorrectly regulated genes, which is probably a contributing factor to the disease,” says Kajsa Paulsson.
The research team is now moving on to find out exactly how great a proportion of the DNA has a deviant type of folding. The results of the study are important for understanding how hyperdiploid childhood leukaemia arises and what stimulates the cancer process.
“Today, more than 90 percent of all children with ALL are cured with the help of extensive chemotherapy treatment. In the future, we hope we will be able to develop even better forms of treatment which will have fewer side-effects and will increase the chance of being cured even more,” Kajsa Paulsson concludes.
“Proteogenomics and Hi-C reveal transcriptional dysregulation in high hyperdiploid childhood acute lymphoblastic leukemia”
MinjunYang, Mattias Vesterlund, Ioannis Siavelis, Larissa H. Moura-Castro, Anders Castor, Thoas Fioretos, Rozbeh Jafari, Henrik Lilljebjörn, Duncan T. Odom, Linda Olsson, Naveen Ravi, Eleanir L. Woodward, Louise Harewood, Janne Lehtiö and Kajsa Paulsson.
Nature Communications 3 April 2019, https://doi.org/10.1038/s41467-019-09469-3
Brief facts about the study: Basic research. Subject: cancer, leukaemia. Study design: quantitative study, research-initiated study
Contact: Kajsa Paulsson, researcher at the Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, 046 2226995,
The study has been financed by funding from Barncancerfonden, Cancerfonden, Swedish Research Council, Kungliga fysiografiska sällskapet i Lund, Stiftelsen Felix Mindus’ contribution to research on leukaemia, Dr Åke Olsson’s Foundation for Research on Haematology, ALF funding, Cancer Research UK, the Wellcome trust and the European Research Council.