Cdx4 is dispensable for murine adult hematopoietic stem cells but promotes MLL-AF9-mediated leukemogenesis.
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.
Koo
Sumin
S
INSERM U985, Institut Gustave Roussy, Université Paris XI, 39 rue Camille Desmoulins, Villejuif, France.
Huntly
Brian J
BJ
Wang
Yuan
Y
Chen
Jing
J
Brumme
Kristina
K
Ball
Brian
B
McKinney-Freeman
Shannon L
SL
Yabuuchi
Akiko
A
Scholl
Claudia
C
Bansal
Dimple
D
Zon
Leonard I
LI
Fröhling
Stefan
S
Daley
George Q
GQ
Gilliland
D Gary
DG
Mercher
Thomas
T
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
C084563:Cdx4 protein, mouse; D018398:Homeodomain Proteins; C551356:MLL-AF9 fusion protein, mouse; D015514:Oncogene Proteins, Fusion