Resistance of mature T cells to oncogene transformation.
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 DeltaTrkA, 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.
Newrzela
Sebastian
S
Georg-Speyer-Haus, Institute for Biomedical Research, Frankfurt, Germany. newrzela@em.uni-frankfurt.de
Cornils
Kerstin
K
Li
Zhixiong
Z
Baum
Christopher
C
Brugman
Martijn H
MH
Hartmann
Marianne
M
Meyer
Johann
J
Hartmann
Sylvia
S
Hansmann
Martin-Leo
ML
Fehse
Boris
B
von Laer
Dorothee
D
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D015458:Leukemia, T-Cell / Q000209:etiology; D016399:Lymphoma, T-Cell / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000209:etiology; D009857:Oncogenes / Q000235:genetics; D013601:T-Lymphocytes / Q000473:pathology*; D014161:Transduction, Genetic