Insertional Oncogenesis after Retroviral Gene Transfer in Hematopoietic Stem Cells

Abstract

This thesis is focuses on the insertional oncogenesis brought about by gamma-retroviral vector insertions. In hematopoietic gene therapy, gamma-retroviral vectors can be used to deliver therapeutic transgenes into target cells of patients with monogenic disorders, which has been successfully shown in three human diseases. The addition of the therapeutic gene to the host cell genome has the opportunity to cure the disorder. The mechanism that allows insertion of the transgene in the host cell genome can unfortunately also introduce deregulation of the genes surrounding the insertion site, sometimes with leukemia as a result. In the studies described here, the insertion profiles in mouse or human hematopoietic cells were analyzed and the frequency of oncogenic mutations was determined. In addition, software that allows automated determination and annotation of retroviral insertion sites was developed.