Distinct genomic integration of MLV and SIV vectors in primate hematopoietic stem and progenitor cells

Peiman Hematti; Bum Kee Hong; Cole Ferguson; Rima Adler; Hideki Hanawa; Stephanie Sellers; Ingeborg E. Holt; Craig E Eckfeldt; Yugal Sharma; Manfred Schmidt; Christof Von Kalle; Derek A. Persons; Eric M. Billings; Catherine M. Verfaillie; Arthur W. Nienhuis; Tyra G. Wolfsberg; Cynthia E. Dunbar; Boris Calmels

doi:10.1371/journal.pbio.0020423

Distinct genomic integration of MLV and SIV vectors in primate hematopoietic stem and progenitor cells

Peiman Hematti, Bum Kee Hong, Cole Ferguson, Rima Adler, Hideki Hanawa, Stephanie Sellers, Ingeborg E. Holt, Craig E Eckfeldt, Yugal Sharma, Manfred Schmidt, Christof Von Kalle, Derek A. Persons, Eric M. Billings, Catherine M. Verfaillie, Arthur W. Nienhuis, Tyra G. Wolfsberg, Cynthia E. Dunbar, Boris Calmels

Medicine - Hematology, Oncology, Transplant

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231 Scopus citations

Abstract

Murine leukemia virus (MLV)-derived vectors are widely used for hematopoietic stem cell (HSC) gene transfer, but lentiviral vectors such as the simian immunodeficiency virus (SIV) may allow higher efficiency transfer and better expression. Recent studies in cell lines have challenged the notion that retroviruses and retroviral vectors integrate randomly into their host genome. Medical applications using these vectors are aimed at HSCs, and thus large-scale comprehensive analysis of MLV and SIV integration in long-term repopulating HSCs is crucial to help develop improved integrating vectors. We studied integration sites in HSCs of rhesus monkeys that had been transplanted 6 mo to 6 y prior with MLV- or SIV-transduced CD34⁺ cells. Unique MLV (491) and SIV (501) insertions were compared to a set of in silico-generated random integration sites. While MLV integrants were located predominantly around transcription start sites, SIV integrants strongly favored transcription units and gene-dense regions of the genome. These integration patterns suggest different mechanisms for integration as well as distinct safety implications for MLV versus SIV vectors. Copyright:

Original language	English (US)
Journal	PLoS biology
Volume	2
Issue number	12
DOIs	https://doi.org/10.1371/journal.pbio.0020423
State	Published - Dec 2004

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Hematti, P., Hong, B. K., Ferguson, C., Adler, R., Hanawa, H., Sellers, S., Holt, I. E., Eckfeldt, C. E., Sharma, Y., Schmidt, M., Von Kalle, C., Persons, D. A., Billings, E. M., Verfaillie, C. M., Nienhuis, A. W., Wolfsberg, T. G., Dunbar, C. E., & Calmels, B. (2004). Distinct genomic integration of MLV and SIV vectors in primate hematopoietic stem and progenitor cells. PLoS biology, 2(12). https://doi.org/10.1371/journal.pbio.0020423

Hematti, P, Hong, BK, Ferguson, C, Adler, R, Hanawa, H, Sellers, S, Holt, IE, Eckfeldt, CE, Sharma, Y, Schmidt, M, Von Kalle, C, Persons, DA, Billings, EM, Verfaillie, CM, Nienhuis, AW, Wolfsberg, TG, Dunbar, CE & Calmels, B 2004, 'Distinct genomic integration of MLV and SIV vectors in primate hematopoietic stem and progenitor cells', PLoS biology, vol. 2, no. 12. https://doi.org/10.1371/journal.pbio.0020423

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abstract = "Murine leukemia virus (MLV)-derived vectors are widely used for hematopoietic stem cell (HSC) gene transfer, but lentiviral vectors such as the simian immunodeficiency virus (SIV) may allow higher efficiency transfer and better expression. Recent studies in cell lines have challenged the notion that retroviruses and retroviral vectors integrate randomly into their host genome. Medical applications using these vectors are aimed at HSCs, and thus large-scale comprehensive analysis of MLV and SIV integration in long-term repopulating HSCs is crucial to help develop improved integrating vectors. We studied integration sites in HSCs of rhesus monkeys that had been transplanted 6 mo to 6 y prior with MLV- or SIV-transduced CD34+ cells. Unique MLV (491) and SIV (501) insertions were compared to a set of in silico-generated random integration sites. While MLV integrants were located predominantly around transcription start sites, SIV integrants strongly favored transcription units and gene-dense regions of the genome. These integration patterns suggest different mechanisms for integration as well as distinct safety implications for MLV versus SIV vectors. Copyright:",

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Distinct genomic integration of MLV and SIV vectors in primate hematopoietic stem and progenitor cells

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