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Preselection of transduced murine hematopoietic stem cell populations leads
to increased long-term stability and expression of the human multiple drug
resistance gene
C Richardson and A Bank
College of Physicians and Surgeons, Department of Genetics and Development,
Columbia University, New York, NY 10032, USA.
We have been using the human multiple drug resistance (MDR) gene to
transduce murine hematopoietic cells via retroviruses as a model system for
potential human gene therapy. In this paper, we show that transplantation
of MDR-transduced midgestational fetal liver cells (FLCs) into lethally
irradiated mice leads to the continued presence and expression of the human
MDR gene in the short-lived granulocyte- macrophages of recipients'
peripheral blood (PB) for up to 12 months. We have also shown the ability
of this retroviral system to efficiently transduce several murine FLC
subpopulations enriched for hematopoietic stem cells (FL-HSCs) both (1)
short-term by MDR-polymerase chain reaction analysis of individual day 12
colony-forming unit-spleen and (2) long-term by in vivo maintenance of MDR
and expression of its product, p-glycoprotein, up to 1 year in PB. More
highly enriched FL- HSC subpopulations show the greatest number of
circulating granulocyte- macrophage cells expressing MDR long-term. These
studies also show that preselection by fluorescence-activated cell sorting
of MDR-transduced and -expressing cells before transplant significantly
increases the percentage of circulating granulocyte-macrophage cells that
express MDR at all time points analyzed posttransplant as compared with
unsorted cells transduced in the same manner (P < .01). These results
have potentially significant implications for future human gene therapy
trials.
Volume 86,
Issue 7,
pp. 2579-2589,
10/01/1995
Copyright © 1995 by The American Society of Hematology
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