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Development of a retroviral construct containing a human mutated
dihydrofolate reductase cDNA for hematopoietic stem cell transduction
MX Li, D Banerjee, SC Zhao, BI Schweitzer, S Mineishi, E Gilboa and JR Bertino
Program of Molecular Pharmacology and Therapeutics, Sloan-Kettering
Institute for Cancer Research, New York, NY.
A double-copy Moloney leukemia virus-based retroviral construct containing
both the NeoR gene and a mutant human dihydrofolate reductase (DHFR) cDNA
(Ser31 mutant) was used to transduce NIH 3T3 and mouse bone marrow (BM)
progenitor cells. This resulted in increased resistance of these cells to
methotrexate (MTX). The transduced BM progenitor cells were returned to
lethally irradiated mice. The recipients transplanted with marrow cells
infected with the recombinant virus showed protection from lethal MTX
toxicity as compared with mock- infected animals. Evidence for integration
of the proviral DNA was obtained by amplification of proviral DNA by
polymerase chain reaction (PCR) and Southern analysis. Sequencing a portion
of the PCR-amplified human DHFR cDNA showed the presence of the mutation.
These studies with the human Ser31 mutant DHFR cDNA gave results comparable
with those obtained with the mutant murine DHFR cDNA (Leu to Arg22) in
developing MTX-resistant BM. The Ser31 mutant human DHFR cDNA is currently
being tested for infection of human CD34+ human BM and peripheral blood
stem cells in vitro.
Volume 83,
Issue 11,
pp. 3403-3408,
06/01/1994
Copyright © 1994 by The American Society of Hematology
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