Preventing leukemia in kids with Down Syndrome

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Canadian researchers are closing in on understanding the high prevalence of leukemia in Down syndrome patients, paving the way for new therapies to eradicate the cancer of the blood and bone marrow before it has a chance to develop. Their findings could be good news in the fight against pediatric leukemia in all children.

A new study, conducted at the Princess Margaret Cancer Centre in Toronto and published in the journal Science, used a preclinical model to map out precisely how and where the disease originates during fetal development.

Down syndrome is a genetic disorder that occurs when an extra copy of chromosome 21 is produced by a random error during cell division in the early stages of human development. The disease is the most frequent genetic anomaly in Canada, occurring in roughly 1 in every 781 babies born in the country, according to the Down Syndrome Association of Toronto. In addition to the physical traits and developmental delays associated with Down syndrome, this extra chromosome contributes to a 150-fold increase in the risk of a myeloid leukemia diagnosis within the first five years of a newborn’s life.

Researchers have long struggled to understand the exact blood cell type in which leukemia first forms, and which genetic changes make the cell preleukemic before it transforms into acute leukemia.

“A whole sequence of cellular events have already happened before a person is diagnosed with the disease,” said John Dick, co-senior author of the study and a senior scientist at Princess Margaret. “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 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 preclinical model the researchers devised included Down syndrome cells from a human tissue biobank and used an enhanced CRISPR/Cas9 method to alter the genes in blood stem cells and make it possible to track the evolution of the cancer. Newborns with Down syndrome frequently develop a condition known as transient preleukemia that can either disappear shortly after birth or become acute myeloid leukemia over the next four years, following subsequent mutations. The model allowed researchers to track the distinct cellular changes and other genetic events connected to the transition of transient preleukemia from its early beginnings in the fetus all the way into childhood.

They discovered that transient leukemia originates only in long-term hematopoietic stem cells (HSCs) with the GATA1 mutation and occurs as early as the second trimester in a fetus with Down syndrome. Preleukemia does not form in the HSCs of non-Down syndrome samples.

The fact that the cellular origin of pediatric leukemia is confined to HSCs — which have a unique capacity for self-renewal that allows them to regenerate the body’s entire blood system —may hold implications for treating this form of cancer in general, not just in children with Down syndrome.

For transient leukemia to transition into acute leukemia, two mutations must have already occurred: the extra copy of chromosome 21 and the GATA1 mutation. This primes downstream descendants of long-term HSCs to mutate further, said Eric Lechman, co-senior author of the study and an affiliate scientist.

“We actually created a human disease in a preclinical model by showing how the genetically edited as well as the normal human blood stem cells behave in it, and we succeeded in recreating the precise, progressive steps of how leukemia develops,” he said. “We now have a lot of clues as to the genetic abnormalities these mutations are driving when they cause leukemia.”

Researchers also identified a unique protein cell surface marker on altered disease-driving HSCs that prompts the proliferation of cells and were able to target and eradicate preleukemic stem cells before they progressed to acute leukemia using small molecule inhibitors. The therapy holds promise for newborns with Down syndrome and, potentially, for other childhood leukemias known to originate in the womb.

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

Dave Yasvinski is a writer with Healthing.ca

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