Using our recently developed cord blood transduction approach, we are able to generate synthetic T-ALL by de novo transformation of normal human hematopoietic progenitors with activated NOTCH1 in combination with accessory oncogenes (M. Kusakabe et al, Nature Communications, 2019). This model generates polyclonal expansions of pre-leukemia cells in vitro within 3-4 weeks, which then produce clonal T-ALL disease within 3 months after injection into immunodeficient mice. Using this model, we are actively exploring the following areas:
• Epigenetic patterning in human T-ALL. We are characterizing the initial establishment and propagation of epigenetic patterns that direct the process of malignant transformation and clonal establishment. We are performing these studies in collaboration with Martin Hirst at UBC.
• Collaborating pathogenetic pathways in human T-ALL. We are executing shRNA and sgRNA screens to identify functional pathways required for clonal establishment and propagation.
• Cell-of-origin dependent programs T-ALL. By varying the input cell source, we are testing whether distinct types of T-ALL are generated from hematopoietic progenitors derived from cord blood vs. fetal liver vs. post-natal thymus vs. adult bone marrow. We have also done considerable work in this area using mouse tissues, comparing fetal liver and adult bone marrow, and revealed developmental stage-specific induction of autocrine growth factor signaling pathways (V. Giambra et al, Cell Stem Cell, 2018).
• Clonal heterogeneity in human T-ALL. Using a cellular barcoding approach, we are exploring clonal dynamics during tumor establishment and propagation. We are performing this work in collaboration with Connie Eaves at BCCA.
*This work is currently funded by a Terry Fox Research Institute Program Project Grant (2017-2022).