Researchers discover a way to genetically screen for acute myeloid leukemia

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An international team of scientists discovers a technique that predicts healthy individuals who are at risk of developing acute myeloid leukemia (AML), which is an aggressive and often deadly form of blood cancer.

The findings, published in Nature, illuminate the ‘black box of leukemia’ and answer the question of where, when and how the disease begins, says co-principal investigator Dr. John Dick, Senior Scientist at Princess Margaret Cancer Centre, University Health Network.

“We have been able to identify people in the general population who have traces of mutations in their blood that represent the first steps in how normal blood cells begin on a pathway of becoming increasingly abnormal and puts them at risk of progressing to AML. We can find these traces up to 10 years before AML actually develops,” says Dr. Dick, who is a professor, Department of Molecular Genetics, University of Toronto, holds the Canada Research Chair in Stem Cell Biology, and is co-leader of the Acute Leukemia Translational Research Initiative at the Ontario Institute for Cancer Research. “This long-time window gives us the first opportunity to think about how to prevent AML.”

Study author Dr. Sagi Abelson, a post-doctoral fellow in the Dick lab, says: “AML is a devastating disease diagnosed too late, with a 90 per cent mortality rate after the age of 65. Our findings show it is possible to identify individuals in the general population who are at high risk of developing AML through a genetic test on a blood sample. The ultimate goal is to identify these individuals and study how we can target the mutated blood cells long before the disease actually begins.”

The study stems from Dr. Dick’s 2014 discovery that a pre-leukemic stem cell could be found hiding amongst all the leukemia cells that are present in the blood sample taken when a person is first diagnosed with AML. The pre-leukemic stem cell still functions normally but it has taken the first step in generating pathway of cells that became more and more abnormal resulting in AML (Nature, February 12, 2014).

“Our 2014 study predicted that people with early mutations in their blood stem cells, long before the disease appears and makes them sick, should be able to be detected within the general population by testing a blood sample for the presence of the mutation,” says Dr. Dick.

The team extracted the data from more than 100 participants who developed AML six to 10 years after joining the study, plus the data from an age-matched cohort of more than 400 who did not develop the disease.

“We wanted to know if there was any difference between these two groups in the genetics of their ‘normal’ blood samples taken at enrollment,” explains Dr. Dick. “To find out, we developed a gene sequencing tool that captured the most common genes that get altered in AML and sequenced all the 500 blood samples.”

The gene sequencing tool was a success and picked up mutations years before an individual was diagnosed with AML to accurately predict those at risk. Moreover, the team used advanced computational technology to assay the information obtained from routinely collected blood tests taken over 15 years in Israel and housed in a massive database of 3.4 million electronic health records.

The study has linked AML with a common feature of aging called ARCH-age related clonal hematopoiesis, whereby blood stem cells acquire mutations and become a little more proliferative. The majority of people that have ARCH will not develop AML. It is a requirement to have AML, but not the other way around.

The UHN research team was funded by the Leukemia and Lymphoma Society, Ontario Institute for Cancer Research, Canadian Cancer Society, Canadian Institutes for Health Research, International Development Research Centre, Terry Fox Research Institute, Medicine by Design – Canada First Research Excellence Fund, the Benjamin Pearl Fellowship from the McEwen Centre for Regenerative Medicine, the Ontario Ministry of Health and Long-term Care, and The Princess Margaret Cancer Foundation.

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