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Blood, Vol. 92 No. 7 (October 1), 1998:
pp. 2269-2279
Transduction of Murine Bone Marrow Cells With an MDR1 Vector
Enables Ex Vivo Stem Cell Expansion, but These Expanded Grafts
Cause a Myeloproliferative Syndrome in Transplanted Mice
Kevin D. Bunting,
Jacques Galipeau,
David Topham,
Ely Benaim, and
Brian P. Sorrentino
From the Division of Experimental Hematology, the Department of
Immunology, and the Department of Biochemistry, St Jude Children's
Research Hospital, Memphis, TN.
Attempts to expand repopulating hematopoietic cells ex vivo have
yielded only modest amplification in stem cell numbers. We now report
that expression of an exogenous human multi-drug resistance 1 (MDR1)
gene enables dramatic ex vivo stem cell expansion in the presence of
early acting hematopoietic cytokines. Bone marrow cells were transduced
with retroviral vectors expressing either the MDR1 gene or a variant of
human dihydrofolate reductase (DHFR), and then expanded for 12 days in
the presence of interleukin-3 (IL-3), IL-6, and stem cell factor. When
these cells were injected into nonirradiated mice, high levels of
long-term engraftment were only seen with MDR1-transduced grafts. To
verify that expansion of MDR1-transduced repopulating cells had
occurred, competitive repopulation assays were performed using MDR1
expanded grafts. These experiments showed progressive expansion of
MDR1-transduced repopulating cells over the expansion period, with a
13-fold overall increase in stem cells after 12 days. In all of the
experiments, mice transplanted with expanded MDR1-transduced stem cells
developed a myeloproliferative disorder characterized by high
peripheral white blood cell counts and splenomegaly. These results show
that MDR1-transduced stem cells can be expanded in vitro using
hematopoietic cytokines without any drug selection, but enforced stem
cell self-renewal divisions can have adverse consequences.
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