HEMATOPOIESIS AND STEM CELLS Modulation of murine embryonic stem cell–derived CD41c-kit hematopoietic progenitors by ectopic expression of Cdx genes

caudal-like Cdx gene family in mammals, whose homologues regulate hematopoi-etic development in zebrafish. Previ-ously, we reported that overexpression of Cdx4 enhances hematopoietic potential from murine embryonic stem cells (ESCs). Here we compare the effect of ectopic Cdx1, Cdx2, and Cdx4 on the differentia-tion of murine ESC-derived hematopoi-etic progenitors. The 3 Cdx genes differen-tially influence the formation and differentiation of hematopoietic progeni-tors within a CD41c-kit population of embryoid body (EB)–derived cells. Cdx1 and Cdx4 enhance, whereas Cdx2 strongly inhibits, the hematopoietic poten-tial of CD41ckit EB-derived cells, changes that are reflected by effects on hematopoietic lineage-specific and Hox gene expression. When we subject stro-mal cell and colony assay cultures of EB-derived hematopoietic progenitors to ectopic expression of Cdx genes, Cdx4 dramatically enhances, whereas Cdx1 and Cdx2 both inhibit hematopoietic activity, probably by blocking progenitor differen-tiation. These data demonstrate distinct effects of Cdx genes on hematopoietic progenitor formation and differentiation, insights that we are using to facilitate efforts at in vitro culture of hematopoietic progenitors from ESC. The behavior of Cdx genes in vitro suggests how derange-ment of these developmental regulators might contribute to leukemogenesis. (Blood. 2008;111:4944-4953