Murine Leukemia Induced by Retroviral Gene Marking

Li, Zhixiong; Düllmann, Jochen; Schiedlmeier, Bernhard; Schmidt, Manfred; Kalle, Christof von; Meyer, Johann; Förster, M.; Stocking, Carol; Wahlers, Anke; Frank, Oliver; Ostertag, Wolfram; Kühlcke, Klaus; Eckert, Hans-Georg; Fehse, Boris; Baum, Christopher

doi:10.1126/science.1068893

Cited by 600 publications

(410 citation statements)

References 9 publications

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“…Given recent events indicating the development of leukemia due to retroviral insertion in both patients and an animal model, 36,[41][42][43][44] it is tempting to speculate how the pCLPG system would impact neighboring genes after insertion in the host genome. Since the pCLPG system depends on p53 to drive expression, it stands to reason that activation of genes neighboring the insertion point would also be elevated in the presence of p53.…”

Section: Discussionmentioning

confidence: 99%

A novel gene transfer strategy that combines promoter and transgene activities for improved tumor cell inhibition

2005

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Typically, gene transfer strategies utilize a promoter/transgene arrangement that treat these elements independently and do not offer any interplay between them. Our goal was to establish a promoter/transgene combination that would result in improvement in both expression and therapeutic effect by utilizing the transcriptional properties of p53 to drive its own expression as well as act as a tumor suppressor. The pCL retroviral system was modified in the U3 region of the 3 0 LTR by the addition of a p53-responsive sequence (the PG element), creating the pCLPG system. Upon reverse transcription, the 5 0 LTR is converted, as shown here, to a p53-dependent promoter. We also show, using a temperature-sensitive model, that the pCLPG system could be driven by p53 encoded within the virus construct and expression was modulated depending on the p53 phenotype, demonstrating a regulatory feedback loop. Moreover, the pCLPG system was shown to express the transgene at a higher level and to inhibit tumor cell proliferation more robustly than the original pCL system. This novel system employs the transgene to serve two purposes, drive viral expression and inhibit tumor cell proliferation. The pCLPG vectors represent a new gene transfer strategy of synergizing the promoter and transgene activities. Cancer Gene Therapy (2005) 12, 935-946.

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Section: Discussionmentioning

confidence: 99%

A novel gene transfer strategy that combines promoter and transgene activities for improved tumor cell inhibition

2005

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“…Recently, such phenomena were actually observed in a mouse model and in human clinical practice. 42,43 In both cases, oncogenesis seems to be a consequence of the activation of an oncogene adjacent to the integrated provirus. Since insulators serve as boundary elements in chromosomes, they might prevent such unexpected activations of adjacent genes and oncogenesis.…”

Section: Sea Urchin Insulator In Lentiviral Vectormentioning

confidence: 99%

Sea urchin insulator protects lentiviral vector from silencing by maintaining active chromatin structure

et al. 2004

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Suppressed expression of transgenes in vivo is the major obstacle in the gene therapy. For the long-term expression, we utilized a chromatin insulator from sea urchin arylsulfatase (Ars) gene locus (Ars insulator, ArsI), which has been shown to epigenetically regulate gene expression across species. ArsI was able to prevent silencing of the transgene in a myeloid cell line, HL-60, and a murine embryonic stem cell line, CCE, in an orientation-dependent manner, but not in Huh-7, K562 and MCF-7 cells, indicating that the effect of ArsI on gene silencing was cell type dependent. Although anti-silencing effect of ArsI was almost equivalent to that of chicken b-globin insulator, incorporation of ArsI into lentiviral vector had little effect on the virus titer compared with chicken b-globin insulator. Clonal analysis of transduced HL-60 cells revealed that ArsI protects the lentiviral vector from position effects regardless of its orientation. Furthermore, chromatin immunoprecipitation assays revealed that a high acetylation level was observed in the promoter of the insulated vector, whereas that of ArsI was independent of its anti-silencing capacity. In addition to it having little deteriorative effect on the virus titer, the identified anti-silencing effect of ArsI suggested its possibility for application in gene therapy.

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“…21 Deregulation of cell growth can also proceed further following retroviral transduction, leading to transformation and malignancy following the use of retroviral vectors encoding oncogenes or growth factors, [22][23][24] and the location of viral insertion was thought to play a role in the transforming process. There is also evidence that vectors encoding a marker gene, truncated nerve growth factor receptor, can also lead to leukemia, 25 although other studies have not found this to be the case. 26 Of greatest concern are observations that retroviral transduction of hematologic stem cells can lead to malignancy in primates and humans.…”

Section: Introductionmentioning

confidence: 99%

Absence of retroviral vector-mediated transformation of gene-modified T cells after long-term engraftment in mice

Westwood

Murray²,

Trivett³

et al. 2008

Gene Ther

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There is considerable concern regarding the transforming potential of retroviral vectors currently used for gene therapy, with evidence that retroviral integration can lead to leukemia in recipients of gene-modified stem cells. However, it is not clear whether retroviral-mediated transduction of T cells can lead to malignancy. We transduced mouse T cells with a Moloney murine retroviral gene construct and transferred them into congenic mice, which were preconditioned to enhance the engraftment of transferred T cells. Recipients were then observed long-term for evidence of cancer. Transferred T cells persisted in mice throughout life at levels up to 17% with gene copy numbers up to 5.89 Â 10 5 per million splenocytes. Mice receiving gene-modified T cells developed tumors at a similar rate as control mice that did not receive T cells, and tumors in both groups of mice were of a similar range of histologies. Hematological malignancies comprised approximately 60% of cancers, and the remaining cancers consisted largely of carcinomas. Importantly, the incidence of lymphomas was similar in both groups of mice, and no lymphomas were found to be of donor T-cell origin. This study indicates that the use of retroviral vectors to transduce T cells does not lead to malignant transformation.

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Murine Leukemia Induced by Retroviral Gene Marking

Cited by 600 publications

References 9 publications

A novel gene transfer strategy that combines promoter and transgene activities for improved tumor cell inhibition

A novel gene transfer strategy that combines promoter and transgene activities for improved tumor cell inhibition

Sea urchin insulator protects lentiviral vector from silencing by maintaining active chromatin structure

Absence of retroviral vector-mediated transformation of gene-modified T cells after long-term engraftment in mice

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