Modelling the multistep pathogenesis of T-cell acute lymphoblastic leukaemia
Document TypePhD thesis
Access StatusOpen Access
© 2019 Hesham Abdulla
T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive T-cell malignancy that is frequently caused by the overexpression of oncogenic transcription factors. Like many cancers, T-ALL is a heterogeneous disease, with the acquisition of many genetic alterations resulting in multiple clones that contribute to cancer progression. This poses a challenge for therapeutic intervention, as different clones within a tumour can possess different genetic signature and thus possess different levels of sensitivity to therapeutic strategies. Therefore, gaining a better understanding of how these clones arise, is crucial to developing more targeted therapies aimed at these cells. LMO2 is a transcription factor that is overexpressed in approximately 9% of T-ALL cases. The CD2-Lmo2 transgenic mouse model overexpress Lmo2 in the thymus, resulting in a developmental block at the DN3 stage of T-cell development, and subsequent development into T-ALL after a long latency (approximately 10 months). Using these mice, our laboratory has shown Lmo2 confers self-renewal capacity to these developmentally blocked DN3 thymocytes many months before the overt presentation of T-ALL. These self-renewing DN3 thymocytes were termed pre-CSCs due to their ability to self-renew, their capacity to still develop into mature functional T-cells, and not initiate leukaemia for many months when transplanted into recipient mice. This thesis will focus on gaining a better understanding of the multi-step pathogenesis of Lmo2 induced murine T-ALL development. In Chapter Three, we explore the role cellular competition for thymic niche space and signals plays in the Lmo2 induced T-cell developmental block, and Lmo2 induced T-ALL. Using competitive bone marrow transplantation experiments we show that the presence of WT thymic progenitors in the thymus severely hinders the development of Lmo2 transgenic thymic progenitors past the DN2 stage of T-cell development, and their subsequent development into T-ALL. Interestingly, we found that overexpression of Bcl2 in Lmo2 transgenic thymocytes severely abrogated the self-renewal capacity of Lmo2 transgenic thymocytes, and hindered their development into T-ALL. Furthermore, we show that Lmo2 downregulates Il7r in DN2 thymocytes. In Chapter Four, we crossed CD2-Lmo2 transgenic mice with CD2-Il7r transgenic mice to create the CD2-Lmo2;CD2-Il7r double-transgenic mouse line, to investigate the role of Il7r overexpression in the Lmo2 induced developmental block. We found that overexpression of Il7r in Lmo2 transgenic thymocytes does not alleviate the Lmo2 induced DN2, or DN3 developmental block, but does increase the engraftment potential of Lmo2 transgenic DN3 thymocytes. Surprisingly, despite the increase in engraftment potential, Il7r overexpression in Lmo2 transgenic thymocytes resulted in a delay in T-ALL induced death, however Il7r overexpression promoted an immature T-ALL immunophenotype. In Chapter Five, we generated an inducible Lmo2 knockin mouse model in which Lmo2 expression can be inhibited by Dox administration. Using this mouse line, we show that while Lmo2 is still required for the self-renewal of Lmo2 transgenic DN3 thymocytes, Lmo2 is not required for T-ALL maintenance in the majority of Lmo2-Induced T-ALLs.
KeywordsLmo2; T-ALL; competition for thymic niche signals; IL7R; self-renewal
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- Medical Biology - Theses