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Research Highlight | October 21, 2021

Study reveals a new target that suggests leukemia in children with Down syndrome could be prevented

Down syndrome is a genetic disorder caused by a random error in cell division in early human development that results in an extra copy of chromosome 21. For years, researchers have known that this extra copy causes developmental changes in children with Down syndrome, including a 150-fold increased risk of developing myeloid leukemia within the first five years of their life. Yet the mechanism by which this alteration leads to leukemia predisposition has remained unclear—until now.

Thanks to a recent study by TFRI-funded researchers at the Princess Margaret Cancer Centre in Toronto we now know more about the intricate relationship between the extra copy of chromosome 21 and leukemia.  Published in Science (May 2021), the study presents the first analysis of where and how leukemia begins and develops in infants with Down syndrome, paving the way to potentially prevent this cancer in the future.

Using a preclinical model that includes human Down syndrome cells from a human tissue biobank, along with an enhanced CRISPR/Cas9 method for gene alteration in human blood stem cells, the team led by co-senior authors Drs. John Dick (senior scientist at Princess Margaret) and Eric Lechman (affiliate scientist at Princess Margaret) and first author Dr. Elvin Wagenblast (post-doc at Princess Margaret), was able to trace the events and mutations that lead to the development of leukemia in children with Down syndrome.

“A whole sequence of cellular events have already happened before a person is diagnosed with the disease,” explains Dr. Dick, who leads a TFRI PPG focused on cancer stem cells. “For the first time, our model is giving us insight into the human leukemia process. Ultimately, we may be able to prevent the acute illness by treating it in its earliest phase, when it is preleukemic, to prevent its progression to full blown leukemia.”

The study uncovered that as early as the second trimester of gestation some children with Down syndrome developed a precursor to leukemia called transient preleukemia. This condition occurs due to a combination of two mutations: the extra copy of chromosome 21, plus mutations in a gene called GATA1 affecting a type of cell called long-term hematopoietic stem cells (HSCs). While not all children with transient preleukemia develop acute leukemia, some do. This happens only after the first two mutations – the extra copy of chromosome 21 and the GATA1 mutation – are in place and have “primed” the progeny or descendants downstream of the altered long-term HSCs to acquire further mutations, explains Dr. Lechman.

While understanding this is important, it isn’t the only key discovery the team made: the study also revealed CD117/KIT as a unique protein cell surface marker on the altered disease-driving stem cells that causes the cells to proliferate. In the preclinical model and setting, the researchers were able to target and eliminate preleukemic stem cells using small molecule CD117/KIT inhibitors to prevent their progression to acute leukemia.

The researchers note that this preventative strategy could potentially be used in Down syndrome newborns and even expanded to other childhood leukemias that are known to be initiated during fetal development.

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


Mapping the cellular origin and early evolution of leukemia in Down syndrome


Elvin Wagenblast, Joana Araújo, Olga I Gan, Sarah K Cutting, Alex Murison, Gabriela Krivdova, Maria Azkanaz, Jessica L McLeod, Sabrina A Smith, Blaise A Gratton, Sajid A Marhon, Martino Gabra, Jessie J F Medeiros, Sanaz Manteghi, Jian Chen, Michelle Chan-Seng-Yue, Laura Garcia-Prat, Leonardo Salmena, Daniel D De Carvalho, Sagi Abelson, Mohamed Abdelhaleem, Karen Chong, Maian Roifman, Patrick Shannon, Jean C Y Wang, Johann K Hitzler, David Chitayat, John E Dick, Eric R Lechman


This study was partially funded by a Terry Fox New Frontier Program Project Grant in Determinants of Stemness That Underlie High Risk or Relapse Disease