Abstract
The work presented in this thesis focuses on the establishment of novel in vitro and in vivo models to study mechanisms of leukemic transformation and to identify new potential druggable targets. MLL-AF9, an oncogene causing a particular subtype of pediatric leukemia, was chosen as the main model for these studies because of its unique biological features and also because of its high frequency in pediatric leukemias.
We took advantage of an in vivo model in which NSG mice are subcutaneously implanted with ceramic scaffolds seeded with human mesenchymal stromal cells in order to generate a human bone marrow (huBM-sc)-like niche. We established a huBM-sc xenograft model in which the myeloid and lymphoid features of MLL-AF9 leukemias can be studied in detail, both using lenti/retroviral model systems as well as patient samples. Also, the efficacy of novel drugs can be evaluated in these mice. Next, we further improved this in vivo model by using MSCs that we genetically engineered to express important cytokines that we identified being expressed at low levels in MSCs, such as IL3 and TPO. This study indicated that the humanized scaffold xenograft model allows for relatively simple genetic engineering of the BM microenvironment and this will be useful for further functional studies of the importance of niche factors for normal and malignant human hematopoiesis. Lastly, we aimed to identify targetable signaling networks in human MLL-AF9 leukemias and showed that MLL-AF9 cells critically depend on FLT3-ligand induced pathways as well as on BRD3/4 for their survival.
We took advantage of an in vivo model in which NSG mice are subcutaneously implanted with ceramic scaffolds seeded with human mesenchymal stromal cells in order to generate a human bone marrow (huBM-sc)-like niche. We established a huBM-sc xenograft model in which the myeloid and lymphoid features of MLL-AF9 leukemias can be studied in detail, both using lenti/retroviral model systems as well as patient samples. Also, the efficacy of novel drugs can be evaluated in these mice. Next, we further improved this in vivo model by using MSCs that we genetically engineered to express important cytokines that we identified being expressed at low levels in MSCs, such as IL3 and TPO. This study indicated that the humanized scaffold xenograft model allows for relatively simple genetic engineering of the BM microenvironment and this will be useful for further functional studies of the importance of niche factors for normal and malignant human hematopoiesis. Lastly, we aimed to identify targetable signaling networks in human MLL-AF9 leukemias and showed that MLL-AF9 cells critically depend on FLT3-ligand induced pathways as well as on BRD3/4 for their survival.
| Translated title of the contribution | Modelleren van leukemie geïnduceerd door MLL-AF9 translocaties: Identificatie van mechanismen en mogelijke targets |
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| Original language | English |
| Qualification | Doctor of Philosophy |
| Awarding Institution |
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| Supervisors/Advisors |
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| Award date | 5-Feb-2018 |
| Place of Publication | [Groningen] |
| Publisher | |
| Print ISBNs | 978-94-034-0440-0 |
| Electronic ISBNs | 978-94-034-0439-4 |
| Publication status | Published - 2018 |