Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Lifelong blood cell production is maintained by rare precursor (stem) cells that reside in the bone marrow throughout adult life. However, as normal people age, these rare cells become functionally "old". As well, recent findings show that in one of ten people over the age of 70, at least one of these rare cells will have acquired a mutation that causes it to display some features of leukemic cells (such as increased proliferation). Although these mutant cells can still produce normal mature blood cells, the individuals in which they are found are at a much greater risk of eventually developing a full-blown leukemia. The objective of my project is to determine whether the number of times a normal adult blood stem cell divides predisposes it to developing changes associated with cellular aging and a tendency to become leukemic. I will explore this idea by transplanting normal human adult blood stem cells into a type of immunodeficient mouse strain that can support the growth of human blood stem cells better than any previously available mice. I will then chemically treat these mice to stimulate the transplanted human blood stem cells to divide much more frequently than they normally do in a person. I will also use an approach that marks the DNA of each blood stem cell to be transplanted with a unique DNA barcode. I will then be able to track the number and type of blood cells produced by each transplanted blood stem cell and determine whether forcing them to divide frequently causes one to become dominant and possibly mutated. I will also determine whether increased blood stem cell proliferation accelerates the appearance of other signs of cellular aging and whether the cells are more likely to become leukemic. These studies will provide insights into how leukemias arise, and serve as a foundation for future treatment strategies for these currently incurable diseases which affect thousands of Canadians.