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Insertional mutagenesis and clonal dominance: biological and statistical considerations

Gene Therapy volume 15, pages 143–153 (2008)Cite this article

Abstract

Improvements of (retroviral) gene transfer vectors, stem cell isolation and culture techniques as well as transduction protocols eventually resulted not only in the successful genetic modification of cells capable of reconstituting the haematopoietic system in various animal models, but also human beings. This was a conditio sine qua non for the successful application of gene therapy for inherited diseases as meanwhile achieved for severe combined immune deficiencies (SCID-X1, ADA-SCID) and chronic granulomatous disease (CGD). Unexpectedly, in long-term animal experiments as well as in the follow up of patients from the CGD trial, haematopoietic clones bearing insertions in certain gene loci became dominant, which was most apparent in the myeloid blood compartment. Accumulating data strongly suggest that this clonal dominance was due to some growth and/or survival advantage conferred by gene-activating or -suppressing effects of the integrated retroviral vector (insertional mutagenesis). Importantly, such induced clonal dominance seems not to lead to malignant transformation of affected cell clones inadvertently. The latter finding has become the basis for the concept of ‘induced haematopoietic stem cells’, a potentially powerful tool to investigate genes involved in the regulation of mechanisms underlying competitive advantages of stem cells, but also in the multi-step nature of malignant transformation. Here we discuss promises and open issues of this concept as well as the important question of common insertion sites statistics and its pitfalls.

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Acknowledgements

This work has been supported by the Deutsche Forschungsgemeinschaft DFG within the Priority Program SPP1230 by grants to BF (FE568/9-1) and IR (RO 3500/1-1). BF's professorship has been funded by the Deutsche Krebshilfe.

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  1. Clinic for Stem Cell Transplantation, University Medical Centre, Hamburg, Germany

    B Fehse

  2. Experimental Paediatric Haematology and Oncology, Johann Wolfgang Goethe University, Frankfurt, Germany

    B Fehse

  3. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany

    I Roeder

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Fehse, B., Roeder, I. Insertional mutagenesis and clonal dominance: biological and statistical considerations. Gene Ther 15, 143–153 (2008). https://doi.org/10.1038/sj.gt.3303052

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