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http://hdl.handle.net/11375/22897
Title: | Unraveling the selective importance of RNA-binding proteins in malignant hematopoietic stem cells |
Authors: | de Rooij, Laura, PMH |
Advisor: | Hope, Kristin |
Department: | Biochemistry and Biomedical Sciences |
Publication Date: | 2018 |
Abstract: | RNA-binding protein (RBP) directed post-transcriptional control of stem cell fate represents an underexplored mechanism through which stemness and transformation may be regulated in the blood system. Interestingly, a unique set of RBPs was found to be specifically enriched in the leukemic stem cell fractions of human primary acute myeloid leukemia (AML) but repressed in normal primitive hematopoietic cells. By using a CRISPR-Cas9-mediated dropout screening approach, key RBPs essential for in vivo propagation of MLL-AF9/NrasG12D driven AML were identified. With additional loss-of-function strategies in normal and malignant hematopoietic stem and progenitor cells (HSPCs), the therapeutic relevance of the RBP ELAVL1 was furthermore shown. In healthy murine bone marrow, Elavl1 knockdown allowed for the selective sparing of the HSPC fraction in vivo, whereas both the colony-forming capacities and in vivo engraftment of MLL-AF9 cells in both primary and secondary transplant settings was significantly impaired upon Elavl1 disruption. Moreover, decreased proliferation and survival as well as increased differentiation in human AML cells upon Elavl1 downregulation was observed. These results shed light on the potential role of specific RBPs as unique and critical regulators of LSCs, paving the way for identification of important novel therapeutic targets in AML. |
URI: | http://hdl.handle.net/11375/22897 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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deRooij_Laura_PMH_03042018_PhD.pdf | 5.13 MB | Adobe PDF | View/Open |
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