The Hox cofactor and proto-oncogene Pbx1 is required for maintenance of definitive hematopoiesis in the fetal liver

Pbx1 is the product of a proto-oncogene originally discovered at the site o f chromosomal translocations In acute leukemias. It binds DNA as a complex with a broad subset of homeodomain proteins, but its contributions to hemat opoiesis have not been established. This paper reports that Pbx1 is express ed in hematopoietic progenitors during murine embryonic development and tha t its absence results in severe anemia and embryonic lethality at embryonic day 15 (E15) or E16. Definitive myeloerythroid lineages are present in Pbx 1(-/-) fetal livers, but the total numbers of colony-forming cells are subs tantially reduced. Fetal liver hypoplasia reflects quantitative as well as qualitative defects in the most primitive multilineage progenitors and thei r lineage-restricted progeny. Hematopoietic stem cells from Pbx1(-/-) embry os have reduced colony-forming activity and are unable to establish multili neage hematopoiesis In competitive reconstitution experiments. Common myelo id progenitors (CMPs), the earliest known myeloerythroid-restricted progeni tors, are markedly depleted in Pbx1(-/-) embryos at E14 and display clonoge nic defects in erythroid colony formation. Comparative cell-cycle Indexes s uggest that these defects result largely from insufficient proliferation. M egakaryocyte-and erythrocyte-committed progenitors are also reduced in numb er and show decreased erythroid colony-forming potential. Taken together, t hese data Indicate that Pbx1 is essential for the function of hematopoietic progenitors with erythropoietic potential and that Its loss creates a prol iferative constriction at the level of the CMP. Thus, Pbx1 Is required for the maintenance, but not the initiation, of definitive hematopoiesis and co ntributes to the mitotic amplifications of progenitor subsets through which mature erythrocytes are generated.