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Blood. 2003 Mar 1;101(5):1784-9. Epub 2002 Oct 31.

Combined effects of Notch signaling and cytokines induce a multiple log increase in precursors with lymphoid and myeloid reconstituting ability.

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Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.


We investigated whether combined signaling induced by engineered Notch ligands and hematopoietic growth factors influences hematopoietic stem-cell differentiation. We show that incubation of murine marrow precursors with Delta1(ext-IgG), a Notch ligand consisting of the Delta1 extracellular domain fused to the Fc portion of human immunoglobulin G1 (IgG1), and growth factors stem cell factor (SCF), interleukin 6 (IL-6), IL-11, and Flt3-l inhibited myeloid differentiation and promoted a several-log increase in the number of precursors capable of short-term lymphoid and myeloid repopulation. Addition of IL7 promoted early T-cell development, whereas addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) led to terminal myeloid differentiation. These results support a role for combinatorial effects by Notch and cytokine-induced signaling pathways in regulating hematopoietic cell fate and suggest the usefulness of Notch ligand in increasing hematopoietic precursor numbers for clinical stem-cell transplantation.

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