title: Human NUP98-HOXA9 promotes hyperplastic growth of hematopoietic tissues in Drosophila.
abstract: Acute myeloid leukemia (AML) is a complex malignancy with poor prognosis. Several genetic lesions can lead to the disease. One of these corresponds to the NUP98-HOXA9 (NA9) translocation that fuses sequences encoding the N-terminal part of NUP98 to those encoding the DNA-binding domain of HOXA9. Despite several studies, the mechanism underlying NA9 ability to induce leukemia is still unclear. To bridge this gap, we sought to functionally dissect NA9 activity using Drosophila. For this, we generated transgenic NA9 fly lines and expressed the oncoprotein during larval hematopoiesis. This markedly enhanced cell proliferation and tissue growth, but did not alter cell fate specification. Moreover, reminiscent to NA9 activity in mammals, strong cooperation was observed between NA9 and the MEIS homolog HTH. Genetic characterization of NA9-induced phenotypes suggested interference with PVR (Flt1-4 RTK homolog) signaling, which is similar to functional interactions observed in mammals between Flt3 and HOXA9 in leukemia. Finally, NA9 expression was also found to induce non-cell autonomous effects, raising the possibility that its leukemia-inducing activity also relies on this property. Together, our work suggests that NA9 ability to induce blood cell expansion is evolutionarily conserved. The amenability of NA9 activity to a genetically-tractable system should facilitate unraveling its molecular underpinnings.
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Québec, Canada H3C 3J7.
authors.forename: Caroline
authors.initials: C
authors.lastname: Baril
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Québec, Canada H3C 3J7.
authors.forename: Gwenaëlle
authors.initials: G
authors.lastname: Gavory
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Québec, Canada H3C 3J7.
authors.forename: Gawa
authors.initials: G
authors.lastname: Bidla
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Québec, Canada H3C 3J7.
authors.forename: Helene
authors.initials: H
authors.lastname: Knævelsrud
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Québec, Canada H3C 3J7; Département de médecine, Université de Montréal, Canada.
authors.forename: Guy
authors.initials: G
authors.lastname: Sauvageau
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Québec, Canada H3C 3J7; Département de pathologie et de biologie cellulaire, Université de Montréal, Canada. Electronic address: marc.therrien@umontreal.ca.
authors.forename: Marc
authors.initials: M
authors.lastname: Therrien
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000254:growth & development* / Q000378:metabolism*; D006410:Hematopoiesis; D006434:Hemocytes / Q000473:pathology; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D006965:Hyperplasia; D008221:Lymphoid Tissue / Q000254:growth & development* / Q000473:pathology; D008322:Mammals; D008940:Mitotic Index; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism*; D010641:Phenotype; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology
chemical_list: D029721:Drosophila Proteins; D018398:Homeodomain Proteins; D028861:Nuclear Pore Complex Proteins; C097899:homeobox protein HOXA9; C108704:hth protein, Drosophila; C093350:nuclear pore complex protein 98; C438368:Pvr protein, Drosophila; D020794:Receptor Protein-Tyrosine Kinases