title: Functional analysis of the NUP98-CCDC28A fusion protein.
abstract: BACKGROUND
  The nucleoporin gene NUP98 is rearranged in more than 27 chromosomal abnormalities observed in childhood and adult, de novo and therapy-related acute leukemias of myeloid and T-lymphoid origins, resulting in the creation of fusion genes and the expression of chimeric proteins. We report here the functional analysis of the NUP98-coiled-coil domain-containing protein 28A (NUP98-CCDC28A) fusion protein, expressed as the consequence of a recurrent t(6;11)(q24.1;p15.5) translocation.
  
  
  METHODS
  To gain insight into the function of the native CCDC28A gene, we collected information on any differential expression of CCDC28A among normal hematologic cell types and within subgroups of acute leukemia. To assess the in vivo effects of the NUP98-CCDC28A fusion, NUP98-CCDC28A or full length CCDC28A were retrovirally transduced into primary murine bone marrow cells and transduced cells were next transplanted into sub-lethally irradiated recipient mice.
  
  
  RESULTS
  Our in silico analyses supported a contribution of CCDC28A to discrete stages of murine hematopoietic development. They also suggested selective enrichment of CCDC28A in the French-American-British M6 class of human acute leukemia. Primary murine hematopoietic progenitor cells transduced with NUP98-CCDC28A generated a fully penetrant and transplantable myeloproliferative neoplasm-like myeloid leukemia and induced selective expansion of granulocyte/macrophage progenitors in the bone marrow of transplanted recipients, showing that NUP98-CCDC28A promotes the proliferative capacity and self-renewal potential of myeloid progenitors. In addition, the transformation mediated by NUP98-CCDC28A was not associated with deregulation of the Hoxa-Meis1 pathway, a feature shared by a diverse set of NUP98 fusions.
  
  
  CONCLUSIONS
  Our results demonstrate that the recurrent NUP98-CCDC28A is an oncogene that induces a rapid and transplantable myeloid neoplasm in recipient mice. They also provide additional evidence for an alternative leukemogenic mechanism for NUP98 oncogenes.
authors: INSERM U985, Institut Gustave Roussy, Villejuif, France.
authors: Arnaud
authors: A
authors: Petit
authors: Christine
authors: C
authors: Ragu
authors: Gwendoline
authors: G
authors: Soler
authors: Chris
authors: C
authors: Ottolenghi
authors: Caroline
authors: C
authors: Schluth
authors: Isabelle
authors: I
authors: Radford-Weiss
authors: Sylvie
authors: S
authors: Schneider-Maunoury
authors: Isabelle
authors: I
authors: Callebaut
authors: Nicole
authors: N
authors: Dastugue
authors: Harry A
authors: HA
authors: Drabkin
authors: Olivier A
authors: OA
authors: Bernard
authors: Serge
authors: S
authors: Romana
authors: Virginie
authors: V
authors: Penard-Lacronique
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002880:Chromosomes, Human, Pair 11; D002896:Chromosomes, Human, Pair 6; D015870:Gene Expression; D055014:Granulocyte-Macrophage Progenitor Cells / Q000473:pathology; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D009363:Neoplasm Proteins / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics; D021381:Protein Transport; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D014178:Translocation, Genetic
chemical_list: C573228:CCDC28A protein, human; D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; C573229:NUP98-CCDC28A fusion protein, human; D009363:Neoplasm Proteins; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; D020033:Protein Isoforms; D011506:Proteins; C093350:nuclear pore complex protein 98; C088144:HoxA protein