Gene transfer of multidrug resistance into a factor-dependent human hematopoietic progenitor cell line: In vivo model for genetically transferred chemoprotection

Paul Schwarzenberger, Sally Spence, Nancy Lohrey, Thomas Kmiecik, Dan L. Longo, William J Murphy, Francis W. Ruscetti, Jonathan R. Keller

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

To develop a rapid preclinical in vivo model to study gene transfer into human hematopoietic progenitor cells, MO-7e cells (CD-34+, c-kit+) were infected with multidrug resistance (MDR1)-containing retroviruses and then transplanted into nonobese diabetic severe combined immunodeficient mice (NOD SCID). MO-7e cells infected with a retrovirus encoding the human MDR1 cDNA showed integration, transcription, and expression of the transfered MDR1 gene. This resulted in a 20-fold increase in the resistance of MO-7e cells to paclitaxel in vitro. The expression of the MDR1 gene product was stable over a 6-month period in vitro without selection in colchicine. MO-7e and MDR1- infected MO-7e cells were transplanted into NOD SCID mice to determine whether MDR1 could confer drug resistance in vivo. A sensitive polymerase chain reaction method specific for human sequences was developed to quantitate the level of human cell engraftment in NOD SCID bone marrow (BM) cells. The percentage of human DNA in BM cells from MO-7e-transplanted mice was 10.9% and decreased to 0.7% in mice treated with paclitaxel. The percentage of human DNA in infected-MO-7e transplanted mice was 7.6% and that level was unchanged in mice treated with paclitaxel. These results show that expression of the MDR1 gene in human hemetopoietic progenitor cells can confer functional drug resistance in an in vivo model.

Original languageEnglish (US)
Pages (from-to)2723-2731
Number of pages9
JournalBlood
Volume87
Issue number7
StatePublished - Apr 1 1996
Externally publishedYes

Fingerprint

MDR Genes
Gene transfer
Hematopoietic Stem Cells
Paclitaxel
Genes
Cells
Cell Line
Bone
Inbred NOD Mouse
SCID Mice
Polymerase chain reaction
DNA
Colchicine
Transcription
Pharmaceutical Preparations
Retroviridae
Drug Resistance
Bone Marrow Cells
Complementary DNA
Gene Expression

ASJC Scopus subject areas

  • Hematology

Cite this

Gene transfer of multidrug resistance into a factor-dependent human hematopoietic progenitor cell line : In vivo model for genetically transferred chemoprotection. / Schwarzenberger, Paul; Spence, Sally; Lohrey, Nancy; Kmiecik, Thomas; Longo, Dan L.; Murphy, William J; Ruscetti, Francis W.; Keller, Jonathan R.

In: Blood, Vol. 87, No. 7, 01.04.1996, p. 2723-2731.

Research output: Contribution to journalArticle

Schwarzenberger, P, Spence, S, Lohrey, N, Kmiecik, T, Longo, DL, Murphy, WJ, Ruscetti, FW & Keller, JR 1996, 'Gene transfer of multidrug resistance into a factor-dependent human hematopoietic progenitor cell line: In vivo model for genetically transferred chemoprotection', Blood, vol. 87, no. 7, pp. 2723-2731.
Schwarzenberger, Paul ; Spence, Sally ; Lohrey, Nancy ; Kmiecik, Thomas ; Longo, Dan L. ; Murphy, William J ; Ruscetti, Francis W. ; Keller, Jonathan R. / Gene transfer of multidrug resistance into a factor-dependent human hematopoietic progenitor cell line : In vivo model for genetically transferred chemoprotection. In: Blood. 1996 ; Vol. 87, No. 7. pp. 2723-2731.
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