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Blood, 15 April 2001, Vol. 97, No. 8, pp. 2406-2412
NEOPLASIA
A model of human p210bcr/ABL-mediated chronic
myelogenous leukemia by transduction of primary normal human
CD34+ cells with a BCR/ABL-containing
retroviral vector
Robert C. Zhao,
Yuehua Jiang, and
Catherine M. Verfaillie
From the Department of Medicine, Stem Cell Institute,
and Cancer Center, University of Minnesota, Minneapolis.
Most insights into the molecular mechanisms underlying
transformation by the p210BCR/ABL oncoprotein are derived
from studies in which BCR/ABL cDNA was introduced into hematopoietic or
fibroblast cell lines. However, such cell line models may not represent
all the features of chronic myelogenous leukemia (CML) caused by
additional genetic abnormalities and differences in the biology of cell
lines compared with primary hematopoietic progenitor and stem cells. A
primary human hematopoietic progenitor cell model for CML was developed
by the transduction of b3a2 BCR/ABL cDNA in normal CD34+
cells. Adhesion of BCR/ABL-transduced CD34+ cells to
fibronectin was decreased, but migration over fibronectin was enhanced
compared with that of mock-transduced CD34+ cells. Adhesion
to fibronectin did not decrease the proliferation of BCR/ABL-transduced
CD34+ cells but decreased the proliferation of
mock-transduced CD34+ cells. This was associated with
elevated levels of p27Kip in
p210BCR/ABL-expressing CD34+ cells. In
addition, the presence of p210BCR/ABL
delayed apoptosis after the withdrawal of cytokines and serum. Finally,
significantly more and larger myeloid colony-forming units grew from
BCR/ABL than from mock-transduced CD34+ cells. Thus, the
transduction of CD34+ cells with the b3a2-BCR/ABL cDNA
recreates most, if not all, phenotypic abnormalities seen in primary
CML CD34+ cells. This model should prove useful for the
study of molecular mechanisms associated with the presence of
p210BCR/ABL in CML.
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