Resistance of mature T cells to oncogene transformation.
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Resistance of mature T cells to oncogene transformation. / Newrzela, Sebastian; Cornils, Kerstin; Li, Zhixiong; Baum, Christopher; Brugman, Martijn H; Hartmann, Marianne; Meyer, Johann; Hartmann, Sylvia; Hansmann, Martin-Leo; Fehse, Boris; von Laer, Dorothee.
in: BLOOD, Jahrgang 112, Nr. 6, 6, 2008, S. 2278-2286.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Resistance of mature T cells to oncogene transformation.
AU - Newrzela, Sebastian
AU - Cornils, Kerstin
AU - Li, Zhixiong
AU - Baum, Christopher
AU - Brugman, Martijn H
AU - Hartmann, Marianne
AU - Meyer, Johann
AU - Hartmann, Sylvia
AU - Hansmann, Martin-Leo
AU - Fehse, Boris
AU - von Laer, Dorothee
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 112
SP - 2278
EP - 2286
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 6
M1 - 6
ER -
