Étude de la fusion humaine NUP98-HOXA9 chez la drosophile
Acute myeloid leukemia (AML) is a heterogenous hematopoietic disorder characterized by the accumulation of immature myeloid progenitors or myeloblasts in the blood and bone marrow. Several genetic abnormalities can lead to the disease. One of these corresponds to the NUP98-HOXA9 (NA9) translocation that fuses sequences encoding the N-terminal portion of NUP98 to those encoding the DNA-binding domain of HOXA9. It is a rare translocation associated with poor prognosis, but represents a prototypical case used to study NUP98-HOX chromosomal rearrangements. Despite numerous studies, the molecular mechanisms underlying NA9 leukemogenic activity remain unclear. This thesis seeks to shed light on NA9’s mechanism of action using the fruit fly Drosophila melanogaster as a model organism.  The first chapter introduces, in a first section, hematopoiesis and provides actual knowledge on NA9 translocation. In a second section, Drosophila hematopoiesis as well as compound eye development and its use for genetic screening strategy are addressed. Next chapters are devoted to our research results. A first article shows phenotype characterization induced by expression of the human NA9 oncoprotein in the Drosophila larval hematopoietic system. NA9 markedly enhanced cell proliferation and tissue growth, but did not alter cell fate specification. Reminiscent to NA9 activity in mammals, NA9 strongly collaborates with the MEIS homolog Hth. Moreover, genetic characterization of NA9-induced phenotype suggested interference with Pvr (Flt1-4 RTK homolog) signalling, which is similar to functional interaction observed in mammals between Flt3 and NUP98-HOX fusions in leukemia. Finally, NA9 expression was also found to induce non-cell autonomous affects, raising the possibility that its leukemogenic activity relies on this property. A second manuscript demonstrates the specificity of a NA9-induced phenotype in fly eye and reports a genetic screen to identify novel NA9 functional partners. A total of 29 loci have been isolated and of which, 16 have now been linked to a specific gene. Three of these had previously been shown to contribute to NA9 activity (Rae1, emb, hth). Finally, we focused on the chromatin remodelling factor E(Pc).     Using Drosophila, this study has uncovered several novel functional aspects linked to NA9 activity. In the long term, upon demonstrating their relevance to NA9-mediated AML onset, some of the new players identified here could pave the way to develop targeted therapeutic strategies to improve overall patient survival.
Fusion NUP98-HOXA9 Drosophila melanogaster Pvr Rae1 Emb Hth E(Pc) NUP98-HOXA9 fusion acute myeloid leukemia (AML) Drosophila melanogaster hematopoiesis modifier screen compound eye Pvr Rae1 Emb Hth E(Pc)