Down to the Stem

Understanding the epigenetics of blood stem cells sheds light on new cancer treatments

June 1, 2015

For the past 30 years Dr. John Dick, a blood explorer, has led the way in creating a cellular family tree of how our blood cells mature. Every day our body produces about a trillion new mature blood cells. Each one begins in the bone marrow as a hematopoietic stem cell (HSC), or blood-producing cell, which can mature into one of more than 10 different sub-types of white and red blood cells.1

"Understanding normal blood cell development is crucial to harnessing the regenerative potential of normal blood tissues as well as teasing apart when and how blood cells become cancerous," says Dr. Dick, a senior researcher at Toronto's Princess Margaret Cancer Centre.

Now after years of successfully mapping differences in blood cells based on their genetic profiles and surface characteristics, Dr. Dick's lab is at the forefront of identifying the epigenetic changes at work when a healthy blood stem cell becomes a mature cell type or when a normal cell turns into a leukemic one. Epigenetic changes are those that turn genes on or off without altering the DNA sequence.

Any cancer, whether it's leukemia or lung cancer, involves a mix of cells that vary in terms of their ability to drive tumor growth over the long term and their resistance to therapy.2

Making Blood Cells

While we generally think of blood as being composed of two types of blood cells, white and red, there are more than a dozen intermediate and mature blood cell development stages. All of these different cells start from hematopoietic stem cells (HSC) in the bone marrow. One of Dr. Dick's key research questions is how genetic and epigenetic factors direct the development of HSC to differentiate and form one kind or another of blood cells – or change to become a leukemia cell.

"We've shown that not every cancer cell is equal. There are some cancer cells, including in leukemia, that are more able to keep the cancer going – they have stem cell properties," says Dr. Dick.

In 1994, Dr. Dick's lab group was the first to isolate cancer stem cells in acute myeloid leukemia (AML), and has since shown that these cells are crucial to understanding the initiation and successful treatment of blood cancers.3 In fact, Dr. Dick's research revealed that only this minor subset of cancerous cells can cause leukemia when transplanted in mice.

Only about one-in-a-thousand leukemia cells are stem cells, but they are critical to cancer recurrence. Chemotherapy targets rapidly dividing cells, but cancer stem cells can remain dormant and survive treatment.

Dr. Dick is now exploring the role that epigenetics plays in the "stemness" of cancer stem cells and HSCs. These cells have a special ability to self-renew – that is, they can divide to form daughter stem cells, but at the same time they can mature and develop into any kind of blood cell. By understanding the "stemness" of these cells, researchers may be able to directly target them with improved cancer therapies.4

"By targeting epigenetic mechanisms, we may be able to alter the sensitivity of the general characteristics of cancer stem cells, making these cells more sensitive to therapies to directly induce cell death," says Dr. Ola Hermanson, a neuroscientist at Sweden's Karolinska Institute and one of Dr. Dick's fellow epigenetics researchers. Dr. Hermanson's research focuses on the epigenetic regulation of neural stem cells and their relationship with brain cancers.

Evidence in Action

Dr. Dick and his lab group are already helping show that it's possible to directly target the epigenetic regulation of "stemness" in certain types of cancer cells.5

As with leukemia, colorectal cancer has stem cells – first reported by Dr. Dick and his team in 2007. In a recent study, Dr. Dick and a team of Canadian researchers blocked the action of a key epigenetic protein called BMI-1 that's critical to cancer stem cell self-renewal. The result: by targeting this key "stemness" protein, they prevented self-renewal and stopped growth of colon cancer tumours that had been grafted into mice.6

In another recent study, Dr. Dick and a team of research collaborators found evidence that the extent of "stemness" in patients with AML can help predict a patient's response to treatment and overall survival.7

The researchers examined blood samples from 16 AML patients at Toronto hospitals and used the expression, or activity, of "stemness" genes as a measure of leukemic stem cell activity. The results have since been verified, in yet unpublished research, in more than 1,000 AML patients from around the world.

"What we're trying to figure out now is the role of epigenetics in this," says Dr. Dick, of ongoing research with Japanese colleagues at the University of Tokyo as part of a CIHR-supported project to create an epigenetic road map of healthy blood cells and leukemia.

Footnotes

Footnote 1

Doulatov, S., et al., "Hematopoiesis: A Human Perspective," Cell Stem Cell, 10,2 (2012):120-136. doi: 10.1016/j.stem.2012.01.006.

1

Footnote 2

Kreso, A., and Dick, J., "Evolution of the Cancer Stem Cell Model," Cell Stem Cell, 14,3 (2014):275-291.

2

Footnote 3

Dick, J.E., "Tumor Archaeology: Tracking Leukemic Evolution to Its Origins," Science Translational Medicine, 6,23 (2014):238. doi: 10.1126/scitranslmed.3009168.

3

Footnote 4

Castelo-Branco, G., and Bannister, A., "The epigenetics of cancer: from non-coding RNAs to chromatin and beyond," Briefings in Functional Genomics, 12,3 (2013):161-163. doi: 10.1093/bfgp/elt020.

4

Footnote 5

Kreso, A., et al., "Variable Clonal Repopulation Dynamics Influence Chemotherapy Response in Colorectal Cancer," Science, 339, 6119 (2013):543-548. doi: 10.1126/science.1227670.

5

Footnote 6

Kreso, A., et al., "Self-renewal as a therapeutic target in human colorectal cancer," Nature Medicine,20,1 (2014):29-36. doi:10.1038/nm.3418.

6

Footnote 7

Eppert, K., et al., "Stem cell gene expression programs influence clinical outcome in human leukemia," Nature Medicine, 17,9 (2011):1086-1093. doi:10.1038/nm.2415.

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