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Sun, Ann (Chong)

University of British Columbia

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy with diverse oncogenic drivers, the relative contributions of which remain obscure. Enforced expression of select oncogenes can generate T-ALL in mice; however, mouse models are limited in their value for understanding human disease and there is a paucity of research of leukemogenesis in human cells. Also, drawing meaningful conclusions regarding oncogene effects in either cell lines or patient-derived xenografts can be difficult as results may be confounded by the presence of interfering genetic mutations and precludes observation of leukemia initiation. To advance our understanding of how recurrently mutated T-ALL oncogenes in human cells collaborate to induce malignant transformation, I utilized a “synthetic” model of human T-ALL using a combination of four known T-ALL oncogenes: NOTCH1 (ΔE allele), LMO2, TAL1, and BMI1 (NLTB). To deconstruct the effect of each oncogene, I introduced ectopic expression of all possible combinations of one, two, three, and four oncogenes into healthy human CD34+ umbilical cord blood (CB) hematopoietic stem progenitor cells (HSPCs). I used this approach to investigate 1) the individual and synergistic impacts of each oncogene on leukemic transformation through a range of functional assays to test growth, differentiation, and self-renewal capacities, and 2) the gene expression profiles in pre-leukemic and leukemic cells to determine downstream pathways and identify potential therapeutic targets. I found that even though constitutive activation of NOTCH1 is essential for promoting aggressive proliferation in T-progenitors, it is unable to sustain unlimited growth and induces early exhaustion. For full leukemic transformation, a cooperating oncogene that imparts self-renewal and long-term repopulation capabilities, such as BMI1, is necessary. LMO2 is also capable of this role and can induce transformation of a more immature leukemia when paired with TAL1. LMO2 and TAL1 cooperate to induce the expression of several HSPC genes and the high expression of one gene, MYCN, correlates with immature leukemias and worse survival in T-ALL patients. These findings deepen our comprehension of the mechanisms of human leukemogenesis and establish a framework for assessing the impact of T-ALL gene mutations within a controlled environment, thereby enhancing the precision of drug targeting strategies.

Text

2024-08-29

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/89088

Interdisciplinary Oncology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/