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

T-cell acute lymphoblastic leukemia (T-ALL) is a cancer predominantly affecting children where their immature T-cells multiply uncontrollably. This disease is linked to mutations in various genes causing higher (oncogenes) or lower (tumor suppressors) activity than normal. Some of the commonly known oncogenes implicated in T-ALL are NOTCH1 (N), LMO2 (L), TAL1 (T), and BMI1 (B). Previous researchers have used addition of single oncogenes to create models of T-ALL using mouse blood progenitor cells but so far similar efforts using human cells have been unsuccessful. Differences in mouse and human T-cell biology underscore the importance of a human model of this disease. Our lab recently developed the first human model of T-ALL by forcing human blood progenitor cells isolated from umbilical cord blood to express an 'always-on' form of NOTCH1, and to overexpress LMO2, TAL1, and BMI1. The objective of my project is to determine the importance of each oncogene individually and in combination with each other in the process of transforming healthy cells into disease propagating T-ALL cells. I will test these oncogene combinations in cord blood progenitor cells by growing them in culture to evaluate for increased cell growth and immature characteristics. I will then use sequencing technology to analyze the gene expression profiles of these cells to discover downstream genes affected by each oncogene we tested. The relative importance of these discovered effector genes in leukemic transformation will be determined by combinatorial expression in my T-ALL model. Finally, I will validate the original oncogene combinations and the discovered downstream genes by injecting the cells into immunodeficient mice and monitoring for leukemia development. These studies will help us understand the individual oncogene contributions and downstream effectors in a human T-ALL model and will facilitate discovery of new targets for therapy.