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Therapy

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

Abstract

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 γ-chain (IL2RG), the coding sequence required for correction of X-linked severe combined immunodeficiency. Similar to conventional γ-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 γ-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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Acknowledgements

We thank Marina Cavazzana-Calvo and Alain Fischer (Hopital Necker, Paris) for the MFG.γc plasmid. This study was supported by grants from the Deutsche Forschungsgemeinschaft (DFG SPP1230 to ZL and CB), the European Union (CONSERT to CB), the Bundesministerium für Bildung und Forschung (BMBF TreatID to CB) and the National Cancer Institute (R01-CA107492-01A2, to CB). AS was supported by the Else-Kröner Foundation.

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Correspondence to C Baum.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Modlich, U., Schambach, A., Brugman, M. et al. Leukemia induction after a single retroviral vector insertion in Evi1 or Prdm16. Leukemia 22, 1519–1528 (2008). https://doi.org/10.1038/leu.2008.118

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