title: NUP98 fusion oncoproteins promote aneuploidy by attenuating the mitotic spindle checkpoint.
abstract: NUP98 is a recurrent fusion partner in chromosome translocations that cause acute myelogenous leukemia. NUP98, a nucleoporin, and its interaction partner Rae1, have been implicated in the control of chromosome segregation, but their mechanistic contributions to tumorigenesis have been unclear. Here, we show that expression of NUP98 fusion oncoproteins causes mitotic spindle defects and chromosome missegregation, correlating with the capability of NUP98 fusions to cause premature securin degradation and slippage from an unsatisfied spindle assembly checkpoint (SAC). NUP98 fusions, unlike wild-type NUP98, were found to physically interact with the anaphase promoting complex/cyclosome (APC/C)(Cdc20) and to displace the BubR1 SAC component, suggesting a possible mechanistic basis for their interference with SAC function. In addition, NUP98 oncoproteins displayed a prolonged half-life in cells. We found that NUP98 stability is controlled by a PEST sequence, absent in NUP98 oncoproteins, whose deletion reproduced the aberrant SAC-interfering activity of NUP98 oncoproteins. Together, our findings suggest that NUP98 oncoproteins predispose myeloid cells to oncogenic transformation or malignant progression by promoting whole chromosome instability.
authors.affiliation: Authors' Affiliations: Department of Life Sciences, University of Modena and Reggio Emilia, Modena; and Department of Hematology, University of Perugia, University Hospital S. Maria della Misericordia, Perugia, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Salsi
authors.forename: Silvia
authors.initials: S
authors.lastname: Ferrari
authors.forename: Paolo
authors.initials: P
authors.lastname: Gorello
authors.forename: Sebastian
authors.initials: S
authors.lastname: Fantini
authors.forename: Francesca
authors.initials: F
authors.lastname: Chiavolelli
authors.forename: Cristina
authors.initials: C
authors.lastname: Mecucci
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Zappavigna
mesh_terms: D000782:Aneuploidy; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D043171:Chromosomal Instability / Q000502:physiology; D020090:Chromosome Segregation / Q000235:genetics; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics*; D008938:Mitosis / Q000235:genetics; D028861:Nuclear Pore Complex Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D009857:Oncogenes / Q000502:physiology; D059748:Proteolysis; D064249:Securin / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
chemical_list: C078492:HHEX protein, human; D018398:Homeodomain Proteins; C521093:NUP98-HOXD13 protein, human; D028861:Nuclear Pore Complex Proteins; C465451:Nup98 protein, human; D015514:Oncogene Proteins, Fusion; D064249:Securin; D014157:Transcription Factors; C578002:pituitary tumor-transforming protein 1, human