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Blood, Vol. 95 No. 2 (January 15), 2000:
pp. 430-436
Expansion of genetically modified primary human hemopoietic cells
using chemical inducers of dimerization
Robert E. Richard,
Brent Wood,
Hui Zeng,
Liqing Jin,
Thalia Papayannopoulou, and
C.
Anthony Blau
From the Divisions of Hematology and Medical Genetics, the
Department of Medicine, and the Department of Laboratory Medicine,
University of Washington School of Medicine, Seattle, WA.
The inability to deliver a therapeutic gene to a sufficient
percentage of hematopoietic stem cells is the major obstacle to using
gene therapy to treat blood disorders. Providing genetically corrected
stem cells with a reversible growth advantage could solve this problem.
To this end we have employed small synthetic molecules that can
reversibly dimerize and activate fusion proteins which contain a growth
factor receptor signaling domain. We have shown that the thrombopoietin
receptor (mpl) signaling domain can be used in this system to expand
transduced multipotential progenitor cells from mouse bone marrow. In
the present study we tested a similar retroviral vector in human
CD34-selected cord blood cells. Following transduction, cells cultured
in the presence of the dimerizing molecule AP1903 expanded
13.8- to 186-fold relative to cells cultured in the absence of AP1903.
The cell type that emerged in suspension culture was erythroid.
Contrary to our results in the murine system, cell expansion was
transient. Activation of mpl caused the disappearance of BFU-E followed
by a transient increase in CFU-E. In contrast, mpl activation had no
discernable effect on transduced myeloid progenitor cells.
AP1903-mediated expansion was restricted to transduced cells, as
demonstrated by immunohistochemical staining. These findings indicate
that synthetic dimerizing molecules can be used to expand primary human hematopoietic cells.
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