blood-forming stem cells

24
Apr 2014
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JulieLessard IRIC 2-cropped

Gene that regulates leukemia will take time (and patience) to tame

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While patience is a virtue for most of us, it is an absolute prerequisite for stem cell researchers.

The recent news that scientists have identified a gene called BRG1 that appears to regulate leukemia stem cells marks an important advance in understanding the dread disease.…

While patience is a virtue for most of us, it is an absolute prerequisite for stem cell researchers.

The recent news that scientists have identified a gene called BRG1 that appears to regulate leukemia stem cells marks an important advance in understanding the dread disease. It also signifies years of work by the team led by Dr. Julie Lessard at the Institute for Research in Immunology and Cancer (IRIC) of Université de Montréal.

“About four years,” says Dr. Lessard, pictured left, one of Canada’s leading researchers in the field of hematopoiesis — the art of blood production.

Using mice as subjects, Dr. Lessard’s team found that removing the BRG1 gene left the leukemia stem cells and progenitors unable to survive, divide and make new tumors, permanently shutting down the cancer.  But while they are delighted with their findings, the researchers know they are in for many more years of work.

“We need to identify BRG1 inhibitors that will work in vitro (in test tubes and Petri dishes) and in vivo (with animals and humans),” says Dr. Lessard. “We believe that it is the ATPase activity that is the essential function we need to target for potential drug development, so that’s what we’re going after.”

In essence, that means finding small molecules that can stifle BRG1, the research equivalent to finding a needle in a haystack. Fortunately, IRIC is equipped with computer-driven high throughput screening to search their library of about 120,000 molecules for one that will do the trick. “We are hoping we can get there in the coming years,” she says.

Dr. Lessard’s findings further strengthen Canadian leadership in the field of stem cells and hematopoiesis. It was two Ontario Cancer Institute researchers — Drs. James Till and Ernest McCulloch — who first proved the existence of stem cells in the early 1960s while trying to find new treatments for leukemia. Dr. John Dick, of Toronto’s University Health Network, first identified tumour-initiating cancer stem cells in 1997.

What’s particularly intriguing about Dr. Lessard’s findings is that shutting down the BRG1 gene only appears to affect leukemia-generating stem cells. “Its function in the normal stem cell is rather modest. So you can take the gene out of leukemic cells and it will shut them down without shutting down the other stem cells you need to continue growth.”

While Dr. Lessard is excited about this project, she’s realistic about the amount of time and work involved.

“First of all, we have to have a very solid preclinical product to test in animals.  We think that a therapeutic window must exist. And this is what makes this study more interesting. It will be very exciting to explore in the coming years.”

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13
Feb 2014
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Our gold medal stem cell scientists

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While Canada’s athletes continue to pile up medals at the Winter Olympics in Sochi and prove their prowess on ice and snow, our stem cell scientists are demonstrating that they too are the best in the world.…

While Canada’s athletes continue to pile up medals at the Winter Olympics in Sochi and prove their prowess on ice and snow, our stem cell scientists are demonstrating that they too are the best in the world.

On the same day that 1,000-metre speed skater Denny Morrison came off the bench (courtesy of team mate Gilmore Junio surrendering his spot) to win silver, Dr. John Dick’s team at the University Health Network in Toronto showed the world what the origins of leukemia look like, publishing their findings in the prestigious journal Nature. That news comes hard on the heels of fellow UHN researcher Dr. Gordon Keller’s discovery of a key regulator that controls the formation of blood-forming stem cells, published in the top-tier Cell.

Both papers represent advances in how we understand and may someday treat disease. Without wanting to sound over-the-top patriotic, both prove that, as a nation, we continue to do outstanding work in the field founded by two Canadians — Drs. James Till and Ernest McCulloch — more than 50 years ago.

Essentially, Dr. Dick has identified a “pre-leukemic stem cell” that appears to initiate acute myeloid leukemia (AML) and, because chemotherapy doesn’t eradicate it, allows the disease to come back. Readers of this blog will recall that Dr. Dick was the first in the world to identify cancer stem cells. He proved that just as stem cells produce millions of specialized cells to build and repair tissues and organs (while also renewing themselves), cancer stem cells drive the production of millions of tumour cells (while also replicating themselves).

“What we found is the first normal cell, the cell of origin, that actually sets off the of cascade events, which is going to ultimately lead to leukemia,” Dr. Dick explains in the UHN video above. “So, one of the direct implications and benefits of our findings is that we should be able to detect leukemia before it arises. And, by identifying patients like that earlier, we should be able to follow them and introduce therapy an earlier stage.”

It should be pointed out that this is very early-stage work. To have application in cancer prevention or care, scientists must find a drug that can target a mutation in the gene called DNMT3 that causes these pre-leukemic stem cells to develop. Such a drug would have to be rigorously tested, something that could take years. But it’s still a very important advance.

“What’s John’s given us is something to go after before the disease gets out of hand,” says Dr. Mick Bhatia, Director of the McMaster Cancer and Stem Cell Biology Research Institute. “That’s a huge gift. It’s like stories about the unicorn. He has identified it, now we have to figure out how to capture it. What we have to grapple with is: ‘Are these pre-leukemic cells targetable?’ ‘Can you diagnose them?’ and ‘Can you shut them down before they become leukemic?'”

In his discovery, Dr. Keller, Director of the McEwen Centre for Regenerative Medicine, identified a key regulator controlling the formation of blood-forming stem cells in the early embryo. He focused on retinoic acid, which is produced from vitamin A and is vital in growth. His team demonstrated that the retinoic acid signalling pathway is critical to making blood-forming stem cells. In experiments with mice, the researchers found that blocking the pathway blocked the formation of blood-making stem cells. Activating it pathway set off an upsurge of blood-forming stem cells.

“Our findings have identified a critical regulator for directing pluripotent stem cells to make blood-forming stem cells, bringing us one step closer to our goal of developing a new and unlimited source of these stem cells for transplantation for the treatment of different blood cell diseases,” says Dr. Keller in Medical News Today.

This discovery is also early-stage work, but also very important, says Dr. Bhatia.

“He is capturing a pathway that is critical for when the first blood stem cell is born and how it makes copies of itself — the self-renewal process. That is going to be instrumental in how we move forward clinically.”

While neither finding is a cure for cancer, both are important steps forward on the path to get there. To push the Olympics analogy a bit further, this is like winning a preliminary competition that allows you compete in the medal round.

Except this is not a game and in this medal round, the prize is much more precious than gold.

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