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Blood, 1 May 2002, Vol. 99, No. 9, pp. 3197-3204
HEMATOPOIESIS
Modulation of p210BCR-ABL activity in transduced
primary human hematopoietic cells controls lineage programming
Yves Chalandon,
Xiaoyan Jiang,
Glen Hazlewood,
Slade Loutet,
Eibhlin Conneally,
Allen Eaves, and
Connie Eaves
From the Terry Fox Laboratory, British Columbia Cancer
Agency, and Departments of Medicine, Pathology and Laboratory Medicine,
and Medical Genetics, University of British Columbia, Vancouver,
British Columbia, Canada.
Retroviral transduction of primary hematopoietic cells with human
oncogenes provides a powerful approach to investigating the molecular
mechanisms controlling the normal proliferation and differentiation of
these cells. Here we show that primitive human CD34+ cord
blood cells, including multipotent as well as granulopoietic- and
erythroid-restricted progenitors, can be efficiently transduced with a
MSCV-BCR-ABL-IRES-GFP retrovirus, resulting in the sustained expression
by their progeny of very high levels of tyrosine phosphorylated p210BCR-ABL. Interestingly, even in the presence of growth
factors that supported the exclusive production of granulopoietic cells
from green fluorescent protein (GFP)-transduced control cells,
BCR-ABL-transduced progenitor subpopulations generated large numbers
of erythropoietin-independent terminally differentiating erythroid
cells and reduced numbers of granulopoietic cells. Analyses of
individual clones generated by single transduced cells in both
semisolid and liquid cultures showed this BCR-ABL-induced erythroid
differentiation response to be elicited at a high frequency from all
types of transduced CD34+ cells independent of their
apparent prior lineage commitment status. Additional experiments showed
that this erythroid differentiation response was largely prevented when
the cells were transduced and maintained in the presence of the
BCR-ABL-specific tyrosine kinase inhibitor, STI-571. These findings
indicate that overexpression of BCR-ABL in primary human hematopoietic
cells can activate an erythroid differentiation program in apparently
granulopoietic-restricted cells through a BCR-ABL kinase-dependent
mechanism, thus providing a new molecular tool for elucidating
mechanisms underlying lineage fate determination in human hematopoietic
cells and infidelity in human leukemia.
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