Abstract
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‐β (TGF‐β) 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‐β‐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‐β signaling, the involvement of CDX2 in the perturbation of the interactions between leukemia cells and their microenvironment.
Highlights
Major developmental genes, such as caudal-related homeobox gene-2 (CDX2) [1], have emerged beyond ontogenesis as critical players in cancer
To address the oncogenic potential of ectopic expression of the human CDX2 homeoprotein in the hematopoietic lineage, MxCDX2 mice were generated by intercrossing RsCDX2 [13] and Mx1Cre [14] mice, and the resulting adult animals aged 2–3 months were treated with poly(I:C) to induce CDX2 expression
This study shows that the ectopic expression of CDX2 in the hematopoietic lineage triggers acute leukemia associated with genome instability and profound changes in gene expression patterns
Summary
Major developmental genes, such as caudal-related homeobox gene-2 (CDX2) [1], have emerged beyond ontogenesis as critical players in cancer This homeobox gene has multiple functions during embryonic development including trophectoderm formation, elongation, and patterning of the posterior body, and intestinal specification, before being selectively expressed in the gut epithelium throughout adulthood where it exerts a tumor suppressor role [2,3,4,5,6]. It is ectopically turned on in precancerous metaplastic lesions of the foregut [1] and, beyond the digestive tract, in a high proportion of acute leukemia associated with poor prognosis (see Ref [7] and references therein).
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