Acute myeloid leukemia is associated with retroviral gene transfer to hematopoietic progenitor cells in a rhesus macaque

Seggewiss, Ruth; Pittaluga, Stefania; Adler, Rima L.; Guenaga, F. Javier; Ferguson, Cole; Pilz, Ingo H.; Ryu, Byoung Y.; Sorrentino, Brian P.; Young, W.S.; Donahue, Robert E.; Kalle, Christof von; Nienhuis, Arthur W.; Dunbar, Cynthia E.

doi:10.1182/blood-2005-10-4108

Cited by 128 publications

(106 citation statements)

References 15 publications

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“…Recent in vivo pre-clinical and clinical trial data have highlighted the potential risk of insertional mutagenesis following integration of retroviral DNA into sensitive areas of the host genome in large animals and humans. [1][2][3] However, recent studies have also identified this risk using lentiviruses. 4 Non-integrating lentiviruses (NILVs) have been developed by introducing class 1 mutations into the integrase gene, and may obviate some of these difficulties.…”

Section: Introductionmentioning

confidence: 99%

Efficient gene delivery to the adult and fetal CNS using pseudotyped non-integrating lentiviral vectors

et al. 2009

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Non-integrating lentiviral vectors show considerable promise for gene therapy applications as they persist as long-term episomes in non-dividing cells and diminish risks of insertional mutagenesis. In this study, non-integrating lentiviral vectors were evaluated for their use in the adult and fetal central nervous system of rodents. Vectors differentially pseudotyped with vesicular stomatitis virus, rabies and baculoviral envelope proteins allowed targeting of varied cell populations. Efficient gene delivery to discrete areas of the brain and spinal cord was observed following stereotactic administration. Furthermore, after direct in utero administration (E14), sustained and strong expression was observed 4 months into adulthood. Quantification of transduction and viral copy number was comparable when using nonintegrating lentivirus and conventional integrating vector. These data support the use of non-integrating lentiviral vectors as an effective alternative to their integrating counterparts in gene therapy applications, and highlight their potential for treatment of inherited and acquired neurological disorders.

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Section: Introductionmentioning

confidence: 99%

Efficient gene delivery to the adult and fetal CNS using pseudotyped non-integrating lentiviral vectors

et al. 2009

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“…Transduction of Rhesus macaque CD34 + stem cells with a gene encoding drug resistance led to acute myeloid leukemia in one of seven animals after drug administration. 27 Leukemia or T-cell monoclonality was also observed in 4 of 11 patients who received CD34 + bone marrow cells gene-modified with a retroviral vector encoding the common g-chain of the interleukin-2 receptor (gc) [28][29][30] Vector insertion near the proto-oncogene LMO2 was thought to have played a role in cell transformation in these patients.…”

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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“…[1][2][3][4][5] However, the semi-random vector insertions bear the risk of activating cellular genes by enhancer/promoter sequences contained in the vector. Transforming side effects of g-retroviral gene transfer were observed in mice and nonhuman primates [6][7][8] and also in gene therapy trials treating X-linked severe combined immunodeficiency (SCID-X1) patients. [9][10][11] The insertional activation of cellular genes also influences the growth of hematopoietic cell clones, thus triggering clonal dominance.…”

Section: Introductionmentioning

confidence: 99%

Leukemia induction after a single retroviral vector insertion in Evi1 or Prdm16

et al. 2008

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Insertional activation of cellular proto-oncogenes by replication-defective retroviral vectors can trigger clonal dominance and leukemogenesis in animal models and clinical trials. Here, we addressed the leukemogenic potential of vectors expressing interleukin-2 receptor common c-chain (IL2RG), the coding sequence required for correction of X-linked severe combined immunodeficiency. Similar to conventional c-retroviral vectors, self-inactivating (SIN) vectors with strong internal enhancers also triggered profound clonal imbalance, yet with a characteristic insertion preference for a window located downstream of the transcriptional start site. Controls including lentivirally transduced cells revealed that ectopic IL2RG expression was not sufficient to trigger leukemia. After serial bone marrow transplantation involving 106 C57Bl6/J mice monitored for up to 18 months, we observed leukemic progression of six distinct clones harboring c-retroviral long terminal repeat (LTR) or SIN vector insertions in Evi1 or Prdm16, two functionally related genes. Three leukemic clones had single vector integrations, and identical clones manifested with a remarkably similar latency and phenotype in independent recipients. We conclude that upregulation of Evi1 or Prdm16 was sufficient to initiate a leukemogenic cascade with consistent intrinsic dynamics. Our study also shows that insertional mutagenesis is required for leukemia induction by IL2RG vectors, a risk to be addressed by improved vector design.

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Acute myeloid leukemia is associated with retroviral gene transfer to hematopoietic progenitor cells in a rhesus macaque

Cited by 128 publications

References 15 publications

Efficient gene delivery to the adult and fetal CNS using pseudotyped non-integrating lentiviral vectors

Efficient gene delivery to the adult and fetal CNS using pseudotyped non-integrating lentiviral vectors

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

Leukemia induction after a single retroviral vector insertion in Evi1 or Prdm16

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