title: RNA export factor RAE1 contributes to NUP98-HOXA9-mediated leukemogenesis.
abstract: Chromosomal translocations involving chimeric fusions of the nucleoporin NUP98 protein have often been described in acute myelogenous leukemia (AML). All the fusion proteins have an identical NUP98 N terminus, which contains the GLEBS motif for interaction with the mRNA export factor RAE1 and FG repeats that associate with the transcription factors HDAC1 and p300. It is virtually unknown whether these interaction partners affect leukemogenesis. We previously showed that RAE1 depletion caused aneuploidy, which enhanced tumorigenesis. We speculated that RAE1 may also be directly involved in NUP98 fusion-mediated leukemogenesis. We show here that RNA interference (RNAi)-mediated knockdown of NUP98 caused severe chromosome segregation defects and disrupted RAE1 but not HDAC1 expression and localization. Next, we performed rescue experiments to confirm that the RAE1-NUP98 complex orchestrates proper chromosome segregation. Interestingly, we found diverse behaviors of NUP98 and the leukemogenic fusion protein NUP98-HOXA9 throughout the cell cycle. Strikingly, in NUP98-HOXA9-transfected cells, RAE1 protein were reduced and mis-localized. Our cellular interpretations were further confirmed by NUP98-HOXA9 transgenic mice and the NUP98-HOXA9 AML patient. These data suggest that RAE1 orchestrates NUP98-mediated leukemogenesis and raise the possibility that targeting this negative feedback loop may provide a new strategy for the therapy of aggressive leukemias.
authors.affiliation: Kanazawa University; Kanazawa, Japan.
authors.forename: Tatsuyoshi
authors.initials: T
authors.lastname: Funasaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakano
authors.forename: Yu
authors.initials: Y
authors.lastname: Wu
authors.forename: Chieko
authors.initials: C
authors.lastname: Hashizume
authors.forename: Ling
authors.initials: L
authors.lastname: Gu
authors.forename: Takuro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Pengbo
authors.initials: P
authors.lastname: Zhou
authors.forename: Malcolm A S
authors.initials: MA
authors.lastname: Moore
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sato
authors.forename: Richard W
authors.initials: RW
authors.lastname: Wong
mesh_terms: D000328:Adult; D000818:Animals; D020090:Chromosome Segregation / Q000235:genetics; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology; D057809:HEK293 Cells; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics / Q000502:physiology*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000502:physiology*; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D034521:Nuclear Matrix-Associated Proteins; D028861:Nuclear Pore Complex Proteins; D029543:Nucleocytoplasmic Transport Proteins; C465451:Nup98 protein, human; C490522:RAE1 protein, human; D011993:Recombinant Fusion Proteins; C097899:homeobox protein HOXA9