title: Expression of Leukemia-Associated Nup98 Fusion Proteins Generates an Aberrant Nuclear Envelope Phenotype.
abstract: Chromosomal translocations involving the nucleoporin NUP98 have been described in several hematopoietic malignancies, in particular acute myeloid leukemia (AML). In the resulting chimeric proteins, Nup98's N-terminal region is fused to the C-terminal region of about 30 different partners, including homeodomain (HD) transcription factors. While transcriptional targets of distinct Nup98 chimeras related to immortalization are relatively well described, little is known about other potential cellular effects of these fusion proteins. By comparing the sub-nuclear localization of a large number of Nup98 fusions with HD and non-HD partners throughout the cell cycle we found that while all Nup98 chimeras were nuclear during interphase, only Nup98-HD fusion proteins exhibited a characteristic speckled appearance. During mitosis, only Nup98-HD fusions were concentrated on chromosomes. Despite the difference in localization, all tested Nup98 chimera provoked morphological alterations in the nuclear envelope (NE), in particular affecting the nuclear lamina and the lamina-associated polypeptide 2α (LAP2α). Importantly, such aberrations were not only observed in transiently transfected HeLa cells but also in mouse bone marrow cells immortalized by Nup98 fusions and in cells derived from leukemia patients harboring Nup98 fusions. Our findings unravel Nup98 fusion-associated NE alterations that may contribute to leukemogenesis.
authors.affiliation: Institute of Molecular Biology and Medicine, Université Libre de Bruxelles, Charleroi, Belgium.
authors.forename: Birthe
authors.initials: B
authors.lastname: Fahrenkrog
authors.affiliation: Institute of Molecular Biology and Medicine, Université Libre de Bruxelles, Charleroi, Belgium.
authors.forename: Valérie
authors.initials: V
authors.lastname: Martinelli
authors.affiliation: Institute of Molecular Biology and Medicine, Université Libre de Bruxelles, Charleroi, Belgium.
authors.forename: Nadine
authors.initials: N
authors.lastname: Nilles
authors.affiliation: Department of Biomedicine, University Children's Hospital Basel, Basel, Switzerland.
authors.forename: Gernot
authors.initials: G
authors.lastname: Fruhmann
authors.affiliation: Institute of Molecular Biology and Medicine, Université Libre de Bruxelles, Charleroi, Belgium.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Chatel
authors.affiliation: Department of Biomedicine, University Children's Hospital Basel, Basel, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Juge
authors.affiliation: Biozentrum, Microscopy Center, University of Basel, Basel, Switzerland.
authors.forename: Ursula
authors.initials: U
authors.lastname: Sauder
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, University of Perugia, Perugia, Italy.
authors.forename: Danika
authors.initials: D
authors.lastname: Di Giacomo
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, University of Perugia, Perugia, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mecucci
authors.affiliation: Department of Biomedicine, University Children's Hospital Basel, Basel, Switzerland.
authors.forename: Jürg
authors.initials: J
authors.lastname: Schwaller
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008938:Mitosis; D009685:Nuclear Envelope / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D028861:Nuclear Pore Complex Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D014178:Translocation, Genetic
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; C093413:lamina-associated polypeptide 2; C093350:nuclear pore complex protein 98