Journal
MOLECULAR ONCOLOGY
Volume 15, Issue 9, Pages 2318-2329Publisher
WILEY
DOI: 10.1002/1878-0261.12982
Keywords
acute monoblastic leukemia; BAMBI; ectopic expression; oncogene; tumor suppressor
Categories
Funding
- Inserm
- Ligue contre le Cancer du Haut-Rhin [2017-18]
- Fondation ARC [PJA 20181208021]
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This study demonstrates the strong oncogenic potential of the homeobox gene CDX2 in the hematopoietic lineage, contrasting with its physiological tumor suppressor activity in the gut. CDX2 protein was shown to bind to and activate the transcription of the human BAMBI promoter, indicating its involvement in perturbation of interactions between leukemia cells and their microenvironment.
The intestine-specific caudal-related homeobox gene-2 (CDX2) homeobox gene, while being a tumor suppressor in the gut, is ectopically expressed in a large proportion of acute leukemia and is associated with poor prognosis. Here, we report that turning on human CDX2 expression in the hematopoietic lineage of mice induces acute monoblastic leukemia, characterized by the decrease in erythroid and lymphoid cells at the benefit of immature monocytic and granulocytic cells. One of the highly stimulated genes in leukemic bone marrow cells was BMP and activin membrane-bound inhibitor (Bambi), an inhibitor of transforming growth factor-beta (TGF-beta) signaling. The CDX2 protein was shown to bind to and activate the transcription of the human BAMBI promoter. Moreover, in a leukemic cell line established from CDX2-expressing mice, reducing the levels of CDX2 or Bambi stimulated the TGF-beta-dependent expression of Cd11b, a marker of monocyte maturation. Taken together, this work demonstrates the strong oncogenic potential of the homeobox gene CDX2 in the hematopoietic lineage, in contrast with its physiological tumor suppressor activity exerted in the gut. It also reveals, through BAMBI and TGF-beta signaling, the involvement of CDX2 in the perturbation of the interactions between leukemia cells and their microenvironment.
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