New findings out of the laboratories of UHN’s Drs. Katherine Siminovitch, Jenny Heathcote and Gideon Hirschfield confirm that certain genes involved in primary biliary cirrhosis (PBC)—the most common autoimmune liver disease—have genetic overlap, or involvement, in other autoimmune diseases commonly found in patients with PBC and their families.

Building upon a previous study in 2009 and published in the New England Journal of Medicine, the team conducted subsequent genetic tests on over 1,300 individuals with PBC and 1,800 non-PBC patients to identify potential risk loci, or genetic areas of disease susceptibility. Specifically, findings show that genetic risk or ‘hot spots’ for PBC are genes located in an area that is also involved in the development of systemic lupus erythmatosus, systemic sclerosis and Sjögrens syndrome. Similarly, a second region of interest also shows increased risk and is associated with asthma, Crohn’s disease and type 1 diabetes.

“Importantly, our studies have helped to identify three new genetic risk locations, including MMEL1, which has been associated with risk for rheumatoid arthritis and celiac disease,” explains Dr. Siminovitch. “We have provided important new evidence that demonstrates there are several shared autoimmune susceptibility loci that contribute to the frequent appearance of additional autoimmune diseases.”

Hirschfield GM, Liu X, Han Y, Gorlov IP, Lu Y, Xu C, Lu Y, Chen W, Juran BD, Coltescu C, Mason AL, Milkiewicz P, Myers RP, Odin JA, Luketic VA, Speiciene D, Vincent C, Levy C, Gregersen PK, Zhang J, Heathcote EJ, Lazaridis KN, Amos CI, Siminovitch KA. Nat Genet. 2010 Aug;42(8):655-7. Epub 2010 Jul 18. [Pubmed abstract]. Research supported by the Canadian Institutes of Health Research, the Ontario Research Fund, the Canadian Primary Biliary Cirrhosis Society, the Canadian Foundation for Innovation, the Ben and Hilda Katz Charitable Foundation, the US National Institutes of Health, the American Gastroenterological Association, and the A.J. and Sigismunda Palumbo Charitable Trust.

Hematopoietic stem cells (HSCs) are responsible for life-long blood production and the strategies these cells use to protect against DNA damage are critical to understand in order to learn how the body prevents the development of leukemia (cancer of the blood). Findings from UHN’s Dr. John Dick are providing new insights into how human HSCs respond to DNA damage. These findings further deepen our understanding of the mechanisms HSCs employ to regenerate billions of new blood cells without promoting cancer development. This knowledge is important in designing new approaches to harness HSC for stem cell transplantation to cure human diseases.

“We’ve found some very important data explaining how DNA damage and cell death is regulated in HSCs and, specifically, how p53 and Bcl-2 proteins and regulators of apoptosis, or coordinated cell death, are involved in the process of DNA repair,” says Dr. Dick.

The team used HSC isolated from cord blood and exposed them to clinically relevant levels of radiation, which induces DNA strand breaks (DNA damage). When the team examined the timing required for repair, they found that HSCs delay DNA break rejoining and call the DNA damage response (DDR) network into action to assist with repair or to trigger cell death. As a result HSC are more sensitive to radiation compared to other cells already further along the process of developing into a mature cell.

“This study has shown that the DDR of human HSCs differs in many ways from more mature blood cell populations, and p53 and Bcl-2 function in different ways to help prevent cancer cell development,” explains Dr. Dick. “Young HSCs take longer to repair and p53 helps balance genome stability and cell death following radiation—a delay that could signify that there are specific mechanisms preventing damaged HSCs from further developing. Moreover, these findings underscore the difference of tumour suppression mechanisms between mice and humans, which is an important consideration in the development of new treatments. Future studies will focus on how the new knowledge regarding the action of p53 and Bcl-2 proteins in human HSC could be employed for therapeutic manipulation.”

Milyavsky M, Gan OI, Trottier M, Komosa M, Tabach O, Notta F, Lechman E, Hermans KG, Eppert K, Konovalova Z, Ornatsky O, Domany E, Meyn MS, Dick JE. Cell Stem Cell. 2010 Aug 6;7(2):186-97. Epub 2010 Jul 8. [Pubmed abstract]. Research supported by postdoctoral fellowships from the European Molecular Biology Organization, the European Hematology Association and the Canadian Institutes for Health Research and The Netherland Society for Scientific Research and grants from The Stem Cell Network of National Centers of Excellence, Canadian Cancer Society Research Institute, Terry Fox Foundation, Genome Canada through the Ontario Genomics Institute, the Ontario Institute for Cancer Research, the Premier’s Summit Award through the Ministry of Research and Innovation, the Leukemia and Lymphoma Society, the Canadian Institutes for Health Research, the Canada Research Chairs Program and, in part, by the Ontario Ministry of Health and Long Term Care.