Cdx4 is dispensable for murine adult hematopoietic stem cells but promotes MLL-AF9-mediated leukemogenesis
| Autor: | Stefan Fröhling, Yuan Wang, Shannon McKinney-Freeman, Leonard I. Zon, Brian J. P. Huntly, Dimple Bansal, George Q. Daley, Claudia Scholl, D. Gary Gilliland, Akiko Yabuuchi, Sumin Koo, Jing Chen, Thomas Mercher, Brian Ball, Kristina Brumme |
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| Rok vydání: | 2010 |
| Předmět: |
Oncogene Proteins
Fusion Biology Leukocyte Count Mice Species Specificity White blood cell medicine Animals Progenitor cell Homeodomain Proteins Mice Knockout Leukemia Genes Homeobox Myeloid leukemia Hematopoietic stem cell Hematology medicine.disease Hematopoiesis Cell biology Transplantation Haematopoiesis medicine.anatomical_structure Leukemia Myeloid Immunology Original Article Stem cell |
| Zdroj: | Haematologica. 95:1642-1650 |
| ISSN: | 1592-8721 0390-6078 |
| DOI: | 10.3324/haematol.2010.023168 |
| Popis: | 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.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.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.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. |
| Databáze: | OpenAIRE |
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