16 July 2019

An Anglo-German joint project has identified dozens of genes that contribute to the development of leukaemia in children with Down’s syndrome, it has been announced.

The researchers say their findings point to existing drugs that might improve treatment of the condition.

About 30% of children with Down’s syndrome have an abnormality in the GATA1 gene that puts them at high risk of leukaemia. The researchers set out to identify the further genetic changes that lead 10% of these children to go on to develop overt myeloid leukaemia.

Through genetic screening of samples donated by children with Down’s syndrome, and functional screens in mouse models, the researchers report on 43 genetic changes that lead to the development of leukaemia. They also identify that the JAK inhibitor ruxolitinib could be effective against some cases of Down’s syndrome-associated leukaemia.

The project involved scientists at the University of Oxford, UK, with Hannover Medical School and Martin-Luther-University Halle-Wittenberg in Germany. The findings were reported in the journal Cancer Cell last week.

Professor Paresh Vyas from Oxford's MRC Molecular Haematology Unit, who co-led the study, said that the research opens the possibility of testing children with Down’s syndrome for the additional mutations responsible for disease progression, as well as mutations in GATA1. “This would mean that we could identify the 10% of children who will develop leukaemia more quickly and easily, and importantly reassure 90% of families whose children will not develop leukaemia”, Vyas said.

“The identification of these genetic changes may also mean we can develop and test new treatments specifically targeting the genetic changes we now know are required by the leukaemia - and so develop more targeted treatments with less side effects.”

Dr Mariana Delfino-Machin from the UK Medical Research Council, which part-funded the work, said: “The recent identification of a group of genes linked to leukaemia in children with Down's syndrome is an important first step towards developing early diagnostic tests and identifying effective treatments to help these patients.”

Source: Labuhn, M., Perkins, K., Matzk, S., Varghese, L., Garnett, C., Papaemmanuil, E., Metzner, M., Kennedy, A., Amstislavskiy, V., Risch, T., Bhayadia, R., Samulowski, D., Cruz Hernandez, D., Stoilova, B., Iotchkova, V., Oppermann, U., Scheer, C., Yoshida, K., Schwarzer, A., Taub, J., Crispino, J.D., Weiss, M.J., Hayashi, A., Taga, T., Ito, E., Ogawa, S., Reinhardt, D., Yaspo, M.-L., Campbell, P.J., Roberts, I., Constantinescu, S., Vyas, P., Heckl, D., Klusmann, J.-H. (2019) “Mechanisms Of Progression Of Myeloid Preleukemia To Transformed Myeloid Leukemia In Children With Down Syndrome”, Cancer Cell, available from doi: 10.1016/j.ccell.2019.06.007


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