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Blood, 1 August 2001, Vol. 98, No. 3, pp. 618-626
HEMATOPOIESIS
The Hox cofactor and proto-oncogene Pbx1 is required for
maintenance of definitive hematopoiesis in the fetal liver
Jorge F. DiMartino,
Licia Selleri,
David Traver,
Meri T. Firpo,
Joon Rhee,
Roger Warnke,
Stephen O'Gorman,
Irving
L. Weissman, and
Michael L. Cleary
From the Departments of Pathology, Pediatrics, and
Developmental Biology, Stanford University School of Medicine, CA; the
Reproductive Genetics Unit, Department of Obstetrics and Gynecology,
University of California, San Francisco; and the Gene Expression
Laboratory, The Salk Institute for Biological Studies, La Jolla, CA.
Pbx1 is the product of a proto-oncogene originally discovered at
the site of chromosomal translocations in acute leukemias. It binds DNA
as a complex with a broad subset of homeodomain proteins, but its
contributions to hematopoiesis have not been established. This paper
reports that Pbx1 is expressed in hematopoietic progenitors during
murine embryonic development and that its absence results in severe
anemia and embryonic lethality at embryonic day 15 (E15) or
E16. Definitive myeloerythroid lineages are present in
Pbx1 / fetal livers, but the total numbers
of colony-forming cells are substantially reduced. Fetal liver
hypoplasia reflects quantitative as well as qualitative defects in the
most primitive multilineage progenitors and their lineage-restricted
progeny. Hematopoietic stem cells from Pbx1/
embryos have reduced colony-forming activity and are unable to establish multilineage hematopoiesis in competitive reconstitution experiments. Common myeloid progenitors (CMPs), the earliest known myeloerythroid-restricted progenitors, are markedly depleted in Pbx1/ embryos at E14 and display clonogenic
defects in erythroid colony formation. Comparative cell-cycle indexes
suggest that these defects result largely from insufficient
proliferation. Megakaryocyte- and erythrocyte-committed progenitors are
also reduced in number and show decreased erythroid colony-forming
potential. Taken together, these data indicate that Pbx1 is
essential for the function of hematopoietic progenitors with
erythropoietic potential and that its loss creates a proliferative
constriction at the level of the CMP. Thus, Pbx1 is required for the
maintenance, but not the initiation, of definitive hematopoiesis and
contributes to the mitotic amplifications of progenitor subsets through
which mature erythrocytes are generated.
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