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Blood, 15 April 2002, Vol. 99, No. 8, pp. 2740-2747
HEMATOPOIESIS
Receptor tyrosine kinase, EphB4 (HTK), accelerates
differentiation of select human hematopoietic cells
Zhengyu Wang,
Nobuyuki Miura,
Andres Bonelli,
Pamela Mole,
Nadia Carlesso,
Douglas P. Olson, and
David T. Scadden
From the Experimental Hematology, AIDS Research
Center and MGH Cancer Center, Massachusetts General Hospital, Harvard
Medical School, Boston, MA.
EphB4 (HTK) and its ligand, ephrinB2, are critical for angiogenesis
and result in fatal abnormalities of capillary formation in null mice.
EphB4 was originally identified in human bone marrow CD34+
cells by us and has since been reported to be expressed in erythroid progenitors, whereas the ligand ephrinB2 is expressed in bone marrow
stromal cells. Reasoning that the developmental relationship between
angiogenesis and hematopoiesis implies common regulatory molecules, we
assessed whether EphB4 signaling influences the function and phenotype
of primitive human hematopoietic cells. Ectopically expressed EphB4 in
cell lines of restricted differentiation potential promoted
megakaryocytic differentiation, but not granulocytic or monocytic
differentiation. Primary cord blood CD34+ cells transduced
with EphB4 resulted in the elevated expression of megakaryocytic and
erythroid specific markers, consistent with EphB4 selectively enhancing
some lineage-committed progenitors. In less mature cells, EphB4
depleted primitive cells, as measured by long-term culture-initiating
cells or CD34+CD38 cell numbers, and
increased progenitor cells of multiple cell types. Effects of ectopic
EphB4 expression could be abrogated by either targeted mutations of
select tyrosine residues or by the tyrosine kinase inhibitor,
genistein. These data indicate that EphB4 accelerates the
differentiation of primitive cells in a nonlineage-restricted manner
but alters only select progenitor populations, influencing lineages
linked by common ancestry with endothelial cells. EphB4 enforces
preferential megakaryocytic and erythroid differentiation and may be a
molecular bridge between angiogenesis and hematopoiesis.
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