15 July 2021

Researchers have mapped for the first time how and where leukaemia develops in children with Down’s syndrome, it has been announced.

Researchers at the Princess Margaret Cancer Centre in Toronto, Canada, say their research could eventually help doctors prevent pre-leukaemia in children with Down’s syndrome, and even have potential to transform cancer care in other children.

Children with Down’s syndrome have a 150-fold increased risk of developing myeloid leukaemia in their first five years of life. However, the mechanism by which the extra copy of chromosome 21 leads to leukaemia was unknown, the researchers say.

The study, published in Science, examines the early evolution of leukaemia in Down’s syndrome. The team used a preclinical mouse model that includes human Down’s syndrome cells from a human tissue biobank, and an enhanced CRISPR/Cas9 method for altering genes in human blood stem cells.

The team, led by Princess Margaret Senior Scientist Dr John Dick with colleagues Dr Elvin Wagenblast and Dr Eric Lechman, aimed to map the steps involved in the development of leukaemia in Down’s syndrome.

Dr Dick said: “A whole sequence of cellular events have already happened before a person is diagnosed with the disease.

“You can't tell at that point which sequence of events happened first, you just know that it has already happened. For the first time, our model is giving us insight into the human leukaemia process.

“Ultimately, we may be able to prevent the acute illness by treating it in its earliest phase, when it is preleukaemic, to prevent its progression to full blown leukaemia.”

Transient pre-leukaemia is unique to new-borns with Down’s syndrome. It can either spontaneously disappear within days to months of birth or transform into acute myeloid leukaemia within four years.

In this study, the research team identified the distinct cellular and genetic events related to transient pre-leukaemia, from their beginnings in the foetus to leukaemia in childhood.

They tested a variety of blood cell types and discovered transient preleukemia only originates from long-term haematopoietic stem cells (HSCs), with the GATA1 mutation, as early as the second trimester of a foetus with Down’s syndrome.  The team says because the cellular origin of paediatric leukaemia is limited to only long-term HSCs, their study could have implications for other kinds of childhood leukaemias.

The team also identified CD117/KIT as a unique protein cell surface marker on both pre-leukaemic and leukaemic stem cells. In the preclinical model, they used small molecule CD117/KIT inhibitors to target and eliminate pre-leukemic stem cells and prevent their progression to acute leukaemia.

“The clinical significance of being able to target pre-cancerous lesions and preventing progression to cancer is profound,” said Dr Dick. “It would transform the paediatric cancer field.”


Wagenblast E, Araújo J, Gan OI, Cutting SK, Murison A, Krivdova G, Azkanaz M, McLeod JL, Smith SA, Gratton BA, Marhon SA, Gabra M, Medeiros JJF, Manteghi S, Chen J, Chan-Seng-Yue M, Garcia-Prat L, Salmena L, De Carvalho DD, Abelson S, Abdelhaleem M, Chong K, Roifman M, Shannon P, Wang JCY, Hitzler JK, Chitayat D, Dick JE, Lechman ER. (2021) “Mapping the cellular origin and early evolution of leukemia in Down syndrome.” Science, doi: 10.1126/science.abf6202

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