title: Cdx4 is dispensable for murine adult hematopoietic stem cells but promotes MLL-AF9-mediated leukemogenesis.
abstract: BACKGROUND
  Cdx4 is a homeobox gene essential for normal blood formation during embryonic development in the zebrafish, through activation of posterior Hox genes. However, its role in adult mammalian hematopoiesis has not been extensively studied and its requirement in leukemia associated with Hox gene expression alteration is unclear.
  
  
  METHODS
  We inactivated Cdx4 in mice through either a germline or conditional knockout approach and analyzed requirement for Cdx4 in both normal adult hematopoiesis and leukemogenesis initiated by the MLL-AF9 fusion oncogene.
  
  
  RESULTS
  Here, we report that loss of Cdx4 had a minimal effect on adult hematopoiesis. Indeed, although an increase in white blood cell counts was observed, no significant differences in the distribution of mature blood cells, progenitors or stem cells were observed in Cdx4-deficient animals. In addition, long-term repopulating activity in competitive transplantation assays was not significantly altered. In vitro, B-cell progenitor clonogenic potential was reduced in Cdx4-deficient animals but no significant alteration of mature B cells was detected in vivo. Finally, induction of acute myeloid leukemia in mice by MLL-AF9 was significantly delayed in the absence of Cdx4 in a retroviral transduction/bone marrow transplant model.
  
  
  CONCLUSIONS
  These observations indicate that Cdx4 is dispensable for the establishment and maintenance of normal hematopoiesis in adult mammals. These results, therefore, outline substantial differences in the Cdx-Hox axis between mammals and zebrafish and support the hypothesis that Cdx factors are functionally redundant during mammalian hematopoietic development under homeostatic conditions. In addition, our results suggest that Cdx4 participates in MLL-AF9-mediated leukemogenesis supporting a role for Cdx factors in the pathogenesis of myeloid leukemia.
authors.affiliation: INSERM U985, Institut Gustave Roussy, Université Paris XI, 39 rue Camille Desmoulins, Villejuif, France.
authors.forename: Sumin
authors.initials: S
authors.lastname: Koo
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Huntly
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Kristina
authors.initials: K
authors.lastname: Brumme
authors.forename: Brian
authors.initials: B
authors.lastname: Ball
authors.forename: Shannon L
authors.initials: SL
authors.lastname: McKinney-Freeman
authors.forename: Akiko
authors.initials: A
authors.lastname: Yabuuchi
authors.forename: Claudia
authors.initials: C
authors.lastname: Scholl
authors.forename: Dimple
authors.initials: D
authors.lastname: Bansal
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
authors.forename: Stefan
authors.initials: S
authors.lastname: Fröhling
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Thomas
authors.initials: T
authors.lastname: Mercher
mesh_terms: D000818:Animals; D005801:Genes, Homeobox; D006410:Hematopoiesis; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D007938:Leukemia / Q000209:etiology*; D007951:Leukemia, Myeloid / Q000209:etiology; D007958:Leukocyte Count; D051379:Mice; D018345:Mice, Knockout; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D013045:Species Specificity
chemical_list: C084563:Cdx4 protein, mouse; D018398:Homeodomain Proteins; C551356:MLL-AF9 fusion protein, mouse; D015514:Oncogene Proteins, Fusion