Caudal (Cdx) genes encode homeobox transcription factors that regulate Hox gene expression. There are three mammalian Cdx genes: Cdx1, Cdx2 and Cdx4. Cdx genes have been shown to be involved in embryonic hematopoiesis in zebrafish and murine embryonic stem cells. CDX genes have also been implicated in human hematopoietic malignancies. CDX2 is upregulated in most AML patients and overexpression of Cdx in murine models causes AML. Here, we investigated the normal function of Cdx in adult mammalian hematopoiesis and their interactions with known leukemic oncogenes MLL-AF9 and BCR-ABL using Cdx-deficient genetic mouse models.
We characterized the hematopoietic system of Cdx4 germline and conditional knockout mice and Cdx1 germline knockout mice. We unexpectedly demonstrated that neither Cdx4 nor Cdx1 is essential for normal adult hematopoiesis in vivo. Cdx deficient mice had minimal hematopoietic defects and their hematopoietic stem cells possessed normal repopulating capabilities. Similar results were observed in the double Cdx1/4 mutants, confirming that the loss of Cdx1 and Cdx4 are dispensable for adult mammalian hematopoiesis.
We went on to test whether Cdx4 is necessary for the development of MLL leukemia using a retroviral murine bone marrow transplantation model. We found that the loss of Cdx4 resulted in delayed latency of MLL-AF9 leukemia but was dispensable for leukemia induction. However, the phenotype of the resultant disease in the Cdx4-/- background was altered, with increased expression of lymphoid markers in primary recipients and the development of lymphoid leukemias in half of the secondary recipients. These results suggest a role for Cdx4 in MLL-induced leukemogenesis but it is not necessary for induction of MLL disease.
Finally, we tested whether Cdx genes are necessary for the development of BCR-ABL leukemia. The abrogation of Cdx1 expression by shRNA hairpins decreased proliferation in BCR-ABL cell lines. Using a retroviral bone marrow transplantation model, we found that the combined loss of Cdx1 and Cdx4 effectively reduced the development of BCR-ABL leukemia. However, there were no differences in disease latency or penetrance with Cdx1-/-, Cdx4-/- or Cdx1+/-4-/-, suggesting functional redundancy among Cdx factors in the context of leukemogenesis.
|Advisor:||Gilliland, D. Gary|
|School Location:||United States -- Massachusetts|
|Source:||DAI-B 70/11, Dissertation Abstracts International|
|Subjects:||Molecular biology, Genetics, Oncology|
|Keywords:||Caudal, Gene expression, Hematopoiesis, Leukemogenesis, Transcription factors|
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