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Blood, 15 January 2002, Vol. 99, No. 2, pp. 499-506
HEMATOPOIESIS
Molecular mechanism of transforming growth factor
 -mediated cell-cycle modulation in primary human
CD34+ progenitors
Mo A. Dao,
Joseph Hwa, and
Jan A. Nolta
From the Division of Research Immunology/Bone Marrow
Transplantation, Children's Hospital Los Angeles, and Departments of
Pediatrics and Craniofacial Molecular Biology, University of Southern
California School of Medicine, Los Angeles, CA.
The mechanisms by which transforming growth factor  (TGF-)
exerts a negative effect on cell-cycle entry in primary human hematopoietic stem/progenitor cells were examined at the molecular and
cellular levels. After treatment of primary human CD34+
progenitors with TGF- there was a decrease in the levels of cyclin
D2 protein and an increase in levels of the cyclin-dependent kinase
inhibitor (CDKI) p15 as compared to the levels in untreated cells. The
converse was true after addition of neutralizing anti-TGF- antibody. Administration of TGF- to CD34+ cells in the
presence of cytokines prevented retinoblastoma protein (pRb)
phosphorylation, which occurred in the same cells treated with
cytokines alone or cytokines and anti-TGF- antibody. Neutralization of TGF- during 24 to 48 hours of culture with cytokines
significantly increased the number of colony-forming progenitors, but
did not modulate the human stem cell pool, as measured in 6- to
12-month xenotransplantation assays. Equivalent numbers of human B, T, and myeloid cells were obtained after transplantation of cells treated
with or without neutralization of TGF-.
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