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Dissecting preleukemic mechanisms in a synthetic model of human T-cell acute lymphoblastic leukemia

University of British Columbia

T-cell acute lymphoblastic leukemia (T-ALL) is a blood malignancy that arises from T lymphoid progenitor cells. Even though the overall prognosis is favorable with the current treatment, patients who relapse have considerably worse outcomes. Moreover, pediatric patients suffer from significant long-term chemotherapy side effects. Therefore, we are in need of an improved therapy that targets key carcinogenic molecular mechanisms. There are several models that are commonly used to research T-ALL in vitro and in vivo, including cell lines and mouse models. However, all of them present major limitations that hinder the interpretation of the results in a natural human disease. To solve them, we have previously designed a synthetic T-ALL model developed from oncogene-transduced human cord blood cells. It effectively addresses constraints of other research systems and allows to reproducibly study early and late events in leukemia development. To support the notion that the synthetic model recapitulates bona fide T-ALL, I aimed to characterize it transcriptionally. As a result, I showed that NOTCH1-LMO2-TAL1-BMI1 (NLTB) transduced leukemia is similar to a wide range of patient-derived xenograft samples. Moreover, I discovered that HOXB and VEGF pathways (which are involved in various cancers) are also enriched in preleukemic cells compared to their normal counterparts. Interestingly, both of these pathways are clinically relevant in T-ALL patients, as their components negatively affect event-free survival. Using NLTB synthetic model, I further investigated functional roles of each of these pathways. Notably, I discovered that HOXB3 gene expression promotes preleukemic and leukemic cell growth in vitro. This suggests that it is involved in both initiation and maintenance of T-ALL. On the other hand, while VEGFR3 was overexpressed on the surface of preleukemic cells, it did not show a consistent effect neither on their growth nor on the growth of primary leukemia cells. This encourages further research into alternative mechanisms through which VEGFR3 influences cancer progression. It also suggests that cell context determines downstream effects of a particular pathway. Overall, this study provides a valuable insight into cellular mechanisms that are activated in leukemia initiation and maintenance and can possibly be used in targeted therapy for T-ALL patients.

Text

2020-11-26

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/76596

Interdisciplinary Oncology

University of British Columbia

UBCV

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