Chromosomal rearrangements of the nucleoporin genes NUP214 and NUP98 are recurrent in aggressive cases of acute myeloid and lymphoid leukemias. NUP214 and NUP98 are components of the nuclear pore complex, a giant multiprotein structure that mediates nucleocytoplasmic shuttling. The two nucleoporins are enriched in phenylalanine-glycine (FG) repeats, which form the NPC permeability barrier and are essential for the interaction with nuclear transport receptors. NUP214 and NUP98 exhibit high affinity for the nuclear export receptor chromosomal region maintenance 1 (CRM1), which, alone, mediates the nuclear export of thousands of proteins and ribonucleoproteins. In the first part of this project, we report that the leukemogenic fusion proteins SET-NUP214 and DEK-NUP214 affect nucleocytoplasmic transport by perturbing the localization of essential nuclear transport factors, including endogenous nucleoporins and CRM1 nuclear export complexes. We further demonstrate that the two fusion proteins are sensitive to CRM1 inhibition and that targeted inhibition of nuclear export is sufficient to reduce the cell viability and proliferation of patient-derived cell lines with SET-NUP214 and DEK-NUP214 rearrangements. In the second part of the project, we used proximity-dependent biotin identification (BioID) to study the landscape of the NUP98-HOXA9 and SET-NUP214 environments. Though distinct endogenous binding partners have been documented for NUP214 and NUP98 chimeras, their total interactome has not been fully disclosed. Our results suggest that both fusion proteins interact with major regulators of RNA processing, with translation-associated proteins, and that both chimeras perturb the transcriptional program of the tumor suppressor p53. We further purpose that the two fusion proteins affect distinct cellular processes. According to our results, NUP98-HOXA9 likely perturbs Wnt, MAPK and estrogen receptor signaling pathways, as well as the cytoskeleton, the latter likely due to its interaction with the nuclear export receptor CRM1. Conversely, SET-NUP214 appears to affect cellular metabolism, likely due to the interaction with mitochondrial proteins and metabolic regulators. Overall, this research project provided new data supporting that CRM1 might be a possible therapeutic target in NUP214-related leukemia and revealed new clues on the mechanistic actions of nucleoporin fusion proteins. Hence, our findings might be of particular relevance in the search of new druggable targets for the treatment of nucleoporin-related leukemia. / Doctorat en Sciences / info:eu-repo/semantics/nonPublished
| Identifer | oai:union.ndltd.org:ulb.ac.be/oai:dipot.ulb.ac.be:2013/308901 |
| Date | 08 July 2020 |
| Creators | Rodrigues Mendes, Maria Adélia |
| Contributors | Fahrenkrog, Birthe, Vanhamme, Luc, Marini, Anna Maria, Lafontaine, Denis, Bellefroid, Eric, Kehlenbach, Ralph H., Schwaller, Jürg |
| Publisher | Universite Libre de Bruxelles, Université libre de Bruxelles, Faculté des Sciences – Sciences biologiques, Bruxelles |
| Source Sets | Université libre de Bruxelles |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/doctoralThesis, info:ulb-repo/semantics/doctoralThesis, info:ulb-repo/semantics/openurl/vlink-dissertation |
| Format | 1 v. (236 p.), 3 full-text file(s): application/pdf | application/pdf | application/pdf |
| Rights | 3 full-text file(s): info:eu-repo/semantics/openAccess | info:eu-repo/semantics/closedAccess | info:eu-repo/semantics/restrictedAccess |
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