The non-cluster homeobox gene TLX1 was initially identified at the breakpoint of the t(10;14)(q24;q11) chromosome translocation in the malignant cells. Three independent research groups have generated transgenic mouse models expressing TLX1 in various hemopoietic cells resulting in development of B cell lymphoma and T-ALL. T-ALL tumours were characterized as immature Double Negative or/and Double Positive phenotypes. In addition, all TLX1 transgenic mice showed a long latency for leukemia development suggesting requirement of additional genomic abnormalities for the conversion of premalignant cells to full-blown malignancy.
We hypothesized that unresolved double strand DNA breaks might act as additional genetic mutation and contribute to T-ALL progression in TLX1 overexpressed thymocytes. To address this hypothesis, we generated double mutant IgHμ-TLX1TgPrkdcScid/Scid mice, which accelerated the development of leukemia relative to PrkdcScid/Scid littermates. We identified that multiple genes associated with chromosome segregation, apoptosis and cell cycle progression were aberrantly expressed in IgHμ-TLX1TgPrkdcScid/Scid premalignant thymocytes. We found that IgHμ-TLX1TgPrkdcScid/Scid thymocytes were prone to chromosome instability suggesting malfunction of the mitotic spindle assembly checkpoint.
In addition to T-ALL, 46% of IgHμ-TLX1TgPrkdcScid/Scid mice developed Acute Myeloid Leukemia, suggesting that the cancer initiating effects of TLX1 are not limited to cells of lymphoid origin. Transplantation experiments revealed that T cell acute lymphoblastic leukemia initiating cells (T-ALL-ICs) reside in the thymus of IgHμ-TLX1TgPrkdcScid/Scid mice and T-ALL-ICs were enriched in the c-kit+CD44+CD25- fraction. We showed that T-ALL tumour cells from IgHμ-TLX1TgPrkdcScid/Scid were transplantable and there was a tendency for the latency period of T-ALL development to be reduced with secondary and tertiary transplantations.
We demonstrated that premalignant IgHμ-TLX1TgPrkdcScid/Scid myeloid progenitors exhibited deregulated apoptosis and proliferation. Collectively, our studies demonstrate that TLX1 expression in DNA-PK-deficient cells activats multiple oncogenic pathways leading to apoptosis resistance, accelerated proliferation and deregulation of the spindle assembly checkpoint. We propose that activation of the same pathways supporting survival and proliferation in various cells may be indicative of the universal principles driving TLX1-induced tumourogenesis. Our data provide clinically relevant information of the molecular mechanisms involved in the pathogenesis of leukemia that makes IgHμ-TLX1TgPrkdcScid/Scid mouse model a powerful tool to explore potential treatment options directed to delay disease progression.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/65677 |
| Date | 22 July 2014 |
| Creators | Krutikov, Konstantin |
| Contributors | Hough, Margaret |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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