A team of international researchers led by U of T’s Dr. Tak Mak has demonstrated how a molecule produced by a genetic mutation can cause leukemia – raising hope scientists can prevent the disease by blocking the mutation.
“For the first time, we have demonstrated how a metabolite can cause cancer,” says Professor Mak of the Princess Margaret Cancer Centre, University Health Network. “This sets the stage for developing inhibitors to block the mutation and prevent the production of this disease-initiating enzyme.”
Published July 4 in Nature, the research shows how a metabolite - a molecule which is produced by a mutated metabolic enzyme - can cause one of the most common types of leukemia in adults.
In the lab, Mak’s team genetically engineered a mouse model with the mutation in its blood system to mimic human acute myeloid leukemia (AML). They discovered that the gene mutation launches the perfect storm for the metabolite to trigger the blood system to increase the stem cells pool and reduce mature blood cells in the bone marrow.
The resulting condition creates a situation with similarities to myelodysplastic syndrome – one of the precursors to this type of leukemia.
“This is one of the most common mutations in AML,” says Mak. “We also found that it is the common mutation in about 40% of a specific type of lymphoma.”
The mutation is also known to be involved in about 70-90% of low-grade brain cancers (glioblastomas gliomas) and a variety of other cancers.
Mak, a professor in the Departments of Medical Biophysics and Immunology at U of T, is an internationally acclaimed immunologist renowned for his 1984 discovery of cloning the human T-cell receptor. His research team included scientists at Weill Cornell Medical College, New York City, and Agios Pharmaceuticals, Cambridge, Massachusetts.
The connection between cancer and metabolism has fascinated Mak and scientists at Agios; they were the first to identify the metabolite in research published in Nature (2009) and The Journal of Experimental Medicine (2010).
The metabolite is a by-product of a gene mutation of an enzyme initially discovered in brain cancers in 2008 by American scientists at Johns Hopkins in Baltimore and subsequently also linked to leukemia.
Mak’s interest in the blood system began as a young researcher three decades ago with Drs. Ernest McCulloch and James Till, the acclaimed “fathers of stem cell science” at Ontario Cancer Institute, the research arm of Princess Margaret Hospital, whose 1961 discovery of stem cells launched the new field. Today, Mak is Director of The Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital.
Mak’s research was funded by grants from the Canadian Institutes of Health Research, the Ontario Ministry of Health and Long-Term Care and the Terry Fox Foundation. His research is also supported by The Princess Margaret Hospital Foundation.