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Insertional Mutagenesis Strategies in Cancer Genetics pp 131–165Cite as

Insertional Mutagenesis in Hematopoietic Cells: Lessons Learned from Adverse Events in Clinical Gene Therapy Trials

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Abstract

From an early stage in the development of retroviral vectors for gene therapy applications, there has been a concern that recombinant vectors could elicit cellular transformation by altering expression of either cellular proto-oncogenes or tumor suppressor genes that are proximal to the genomic integration site (Fig. 6.1). This phenomenon, referred to as insertional mutagenesis, was characterized as a property of wild type gammaretroviral viruses (previously known as murine oncoretroviral viruses) which are the prototype virus from which the recombinant vectors used in the majority of the clinical trials described in this chapter were derived (reviewed in [178]). Wild type retroviruses fall into two categories with regards to their transforming properties: Slow transforming and acute transforming retroviruses.

Lars U. Müller and Michael D. Milsom have equally contributed to this work.

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Acknowledgments

We thank Megan Smith, Miriam Edlund and Elise Porter for administrative support and members of our laboratory and the Transatlantic Gene Therapy Consortium for helpful discussions. This work is supported by NIH HL081499.

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  1. Harvard Medical School, Children’s Hospital Boston, Boston, MA, 02115, USA

    Lars U. Müller, Michael D. Milsom & David A. Williams

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  1. Carver College of Medicine, Dept. Anatomy & Cell Biology, University of Iowa, Newton Road 51, Iowa City, 52241, Iowa, USA

    Adam J. Dupuy

  2. Dept. Genetics, Cell Biology &, Development, University of Minnesota, Church St. SE., 321, Minneapolis, 55455, Minnesota, USA

    David A. Largaespada

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Müller, L.U., Milsom, M.D., Williams, D.A. (2011). Insertional Mutagenesis in Hematopoietic Cells: Lessons Learned from Adverse Events in Clinical Gene Therapy Trials. In: Dupuy, A., Largaespada, D. (eds) Insertional Mutagenesis Strategies in Cancer Genetics. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-7656-7_6

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