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Blood, Vol. 93 No. 3 (February 1), 1999:
pp. 838-848
Notch1-Induced Delay of Human Hematopoietic Progenitor Cell
Differentiation Is Associated With Altered Cell Cycle Kinetics
Nadia Carlesso,
Jon C. Aster,
Jeffrey Sklar, and
David T. Scadden
From the Department of Experimental Hematology, Partners AIDS
Research Center and MGH Cancer Center, Massachusetts General Hospital,
Harvard Medical School; and the Department of Pathology, Brigham and
Women's Hospital, Harvard Medical School, Boston, MA.
Hematopoiesis is a balance between proliferation and differentiation
that may be modulated by environmental signals. Notch receptors and
their ligands are highly conserved during evolution and have been shown
to regulate cell fate decisions in multiple developmental systems. To
assess whether Notch1 signaling may regulate human hematopoiesis to
maintain cells in an immature state, we transduced a vesicular
stomatitis virus G-protein (VSV-G) pseudo-typed bicistronic murine stem
cell virus (MSCV)-based retroviral vector expressing a
constitutively active form of Notch1 (ICN) and green fluorescence
protein into the differentiation competent HL-60 cell line and primary
cord blood-derived CD34+ cells. In addition, we observed
endogenous Notch1 expression on the surface of both HL-60 cells and
primary CD34+ cells, and therefore exposed cells to Notch
ligand Jagged2, expressed on NIH3T3 cells. Both ligand-independent and
ligand-dependent activation of Notch resulted in delayed acquisition of
differentiation markers by HL-60 cells and cord blood
CD34+ cells. In addition, primary CD34+
cells retained their ability to form immature colonies, colony-forming unit-mix (CFU-mix), whereas control cells lost this
capacity. Activation of Notch1 correlated with a decrease in the
fraction of HL-60 cells that were in G0/G1
phase before acquisition of a mature cell phenotype. This enhanced
progression through G1 was noted despite preservation of
the proliferative rate of the cells and the overall length of the cell
cycle. These findings show that Notch1 activation delays human
hematopoietic differentiation and suggest a link of Notch
differentiation effects with altered cell cycle kinetics.
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October 4, 1999;
147(1):
105 - 120.
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[Full Text]
[PDF]
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