1. ¹Department of Hematology and Oncology, Hannover Medical School, Hannover, Germany
2. ²Division of Experimental Hematology, Cincinnati Children's Research Foundation, Cincinnati, Ohio 45229, USA
3. ³Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands
4. ⁴Bone Marrow Transplantation, University Hospital Eppendorf, Hamburg, Germany
5. ⁵Institute for Molecular Medicine and Department of Internal Medicine I, University of Freiburg, Freiburg, Germany
6. ⁶Molecular Medicine and Gene Therapy, Lund University Hospital, Lund, Sweden
7. ⁷Institute of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands

Correspondence: David A. Williams, Fax: (513)636-3768. E-mail: david.williams@cchmc.org

Abstract

Recently, unusual forms of leukemias have developed as complications following retroviral transfer of potentially therapeutic genes into hematopoietic cells. A crucial component in the pathogenesis of these complications was the upregulation of a cellular proto-oncogene by random insertion of the retroviral gene transfer vector. These findings have great implications for the genetic manipulation of somatic stem cells in medicine. This review discusses the extent to which the random oncogene activation may have required disease-specific stimuli of the transgene and the hematopoietic milieu to become leukemogenic. Based on these considerations, we propose approaches to risk prediction and prevention.