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 Blood, 15 September 2008, Vol. 112, No. 6, pp. 2278-2286.
Prepublished online as a Blood First Edition Paper on June 19, 2008; DOI 10.1182/blood-2007-12-128751.

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GENE THERAPY

Resistance of mature T cells to oncogene transformation

Sebastian Newrzela1, Kerstin Cornils2, Zhixiong Li3, Christopher Baum3, Martijn H. Brugman3, Marianne Hartmann1, Johann Meyer3, Sylvia Hartmann4, Martin-Leo Hansmann4, Boris Fehse2, and Dorothee von Laer1

1 Georg-Speyer-Haus, Institute for Biomedical Research, Frankfurt; 2 University Hospital of the Johann Wolfgang Goethe-University, Experimental Pediatric Oncology and Hematology, Frankfurt am Main; 3 Hannover Medical School, Department of Experimental Hematology, Hannover; and 4 University of Frankfurt, Department of Pathology, Frankfurt, Germany

Leukemia caused by retroviral insertional mutagenesis after stem cell gene transfer has been reported in several experimental animals and in patients treated for X-linked severe combined immunodeficiency. Here, we analyzed whether gene transfer into mature T cells bears the same genotoxic risk. To address this issue in an experimental "worst case scenario," we transduced mature T cells and hematopoietic progenitor cells from C57BL/6 (Ly5.1) donor mice with high copy numbers of gamma retroviral vectors encoding the potent T-cell oncogenes LMO2, TCL1, or {Delta}TrkA, a constitutively active mutant of TrkA. After transplantation into RAG-1–deficient recipients (Ly5.2), animals that received stem cell transplants developed T-cell lymphoma/leukemia for all investigated oncogenes with a characteristic phenotype and after characteristic latency periods. Ligation-mediated polymerase chain reaction analysis revealed monoclonality or oligoclonality of the malignancies. In striking contrast, none of the mice that received T-cell transplants transduced with the same vectors developed leukemia/lymphoma despite persistence of gene-modified cells. Thus, our data provide direct evidence that mature T cells are less prone to transformation than hematopoietic progenitor cells.


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