Lymphomagenesis in SCID-X1 Mice Following Lentivirus-mediated Phenotype Correction Independent of Insertional Mutagenesis and γc Overexpression
Identifieur interne : 000075 ( Pmc/Corpus ); précédent : 000074; suivant : 000076Lymphomagenesis in SCID-X1 Mice Following Lentivirus-mediated Phenotype Correction Independent of Insertional Mutagenesis and γc Overexpression
Auteurs : Samantha L. Ginn ; Sophia Hy Liao ; Allison P. Dane ; Min Hu ; Jessica Hyman ; John W. Finnie ; Maolin Zheng ; Marina Cavazzana-Calvo ; Stephen I. Alexander ; Adrian J. Thrasher ; Ian E. AlexanderSource :
- Molecular Therapy [ 1525-0016 ] ; 2010.
Abstract
The development of leukemia as a consequence of vector-mediated genotoxicity in gene therapy trials for X-linked severe combined immunodeficiency (SCID-X1) has prompted substantial research effort into the design and safety testing of integrating vectors. An important element of vector design is the selection and evaluation of promoter-enhancer elements with sufficient strength to drive reliable immune reconstitution, but minimal propensity for enhancer-mediated insertional mutagenesis. In this study, we set out to explore the effect of promoter-enhancer selection on the efficacy and safety of human immunodeficiency virus-1-derived lentiviral vectors in γc-deficient mice. We observed incomplete or absent T- and B-cell development in mice transplanted with progenitors expressing γc from the phosphoglycerate kinase (PGK) and Wiscott–Aldrich syndrome (WAS) promoters, respectively. In contrast, functional T- and B-cell compartments were restored in mice receiving an equivalent vector containing the elongation factor-1-α (EF1α) promoter; however, 4 of 14 mice reconstituted with this vector subsequently developed lymphoma. Extensive analyses failed to implicate insertional mutagenesis or γc overexpression as the underlying mechanism. These findings highlight the need for detailed mechanistic analysis of tumor readouts in preclinical animal models assessing vector safety, and suggest the existence of other ill-defined risk factors for oncogenesis, including replicative stress, in gene therapy protocols targeting the hematopoietic compartment.
Url:
DOI: 10.1038/mt.2010.50
PubMed: 20354504
PubMed Central: 2890120
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Lymphomagenesis in SCID-X1 Mice Following Lentivirus-mediated Phenotype Correction Independent of Insertional Mutagenesis and γc Overexpression</title><author><name sortKey="Ginn, Samantha L" sort="Ginn, Samantha L" uniqKey="Ginn S" first="Samantha L" last="Ginn">Samantha L. Ginn</name><affiliation><nlm:aff id="aff1"><institution>Gene Therapy Research Unit of the Children's Medical Research Institute and The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Liao, Sophia Hy" sort="Liao, Sophia Hy" uniqKey="Liao S" first="Sophia Hy" last="Liao">Sophia Hy Liao</name><affiliation><nlm:aff id="aff1"><institution>Gene Therapy Research Unit of the Children's Medical Research Institute and The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Dane, Allison P" sort="Dane, Allison P" uniqKey="Dane A" first="Allison P" last="Dane">Allison P. Dane</name><affiliation><nlm:aff id="aff1"><institution>Gene Therapy Research Unit of the Children's Medical Research Institute and The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Hu, Min" sort="Hu, Min" uniqKey="Hu M" first="Min" last="Hu">Min Hu</name><affiliation><nlm:aff id="aff2"><institution>Centre for Kidney Research of The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Hyman, Jessica" sort="Hyman, Jessica" uniqKey="Hyman J" first="Jessica" last="Hyman">Jessica Hyman</name><affiliation><nlm:aff id="aff3"><institution>Oncology Research Unit of The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Finnie, John W" sort="Finnie, John W" uniqKey="Finnie J" first="John W" last="Finnie">John W. Finnie</name><affiliation><nlm:aff id="aff4"><institution>Institute of Medical and Veterinary Science</institution> Adelaide, South Australia,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Zheng, Maolin" sort="Zheng, Maolin" uniqKey="Zheng M" first="Maolin" last="Zheng">Maolin Zheng</name><affiliation><nlm:aff id="aff1"><institution>Gene Therapy Research Unit of the Children's Medical Research Institute and The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Cavazzana Calvo, Marina" sort="Cavazzana Calvo, Marina" uniqKey="Cavazzana Calvo M" first="Marina" last="Cavazzana-Calvo">Marina Cavazzana-Calvo</name><affiliation><nlm:aff id="aff5"><institution>Paediatric Immunology and Haematology Unit, Hôpital Necker-Enfants Malades</institution> Paris,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Alexander, Stephen I" sort="Alexander, Stephen I" uniqKey="Alexander S" first="Stephen I" last="Alexander">Stephen I. Alexander</name><affiliation><nlm:aff id="aff2"><institution>Centre for Kidney Research of The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Thrasher, Adrian J" sort="Thrasher, Adrian J" uniqKey="Thrasher A" first="Adrian J" last="Thrasher">Adrian J. Thrasher</name><affiliation><nlm:aff id="aff6"><institution>Institute of Child Health, Great Ormond Street Hospital</institution> London,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Alexander, Ian E" sort="Alexander, Ian E" uniqKey="Alexander I" first="Ian E" last="Alexander">Ian E. Alexander</name><affiliation><nlm:aff id="aff1"><institution>Gene Therapy Research Unit of the Children's Medical Research Institute and The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff7"><institution>Discipline of Paediatrics and Child Health, The University of Sydney</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">20354504</idno><idno type="pmc">2890120</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2890120</idno><idno type="RBID">PMC:2890120</idno><idno type="doi">10.1038/mt.2010.50</idno><date when="2010">2010</date><idno type="wicri:Area/Pmc/Corpus">000075</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000075</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Lymphomagenesis in SCID-X1 Mice Following Lentivirus-mediated Phenotype Correction Independent of Insertional Mutagenesis and γc Overexpression</title><author><name sortKey="Ginn, Samantha L" sort="Ginn, Samantha L" uniqKey="Ginn S" first="Samantha L" last="Ginn">Samantha L. Ginn</name><affiliation><nlm:aff id="aff1"><institution>Gene Therapy Research Unit of the Children's Medical Research Institute and The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Liao, Sophia Hy" sort="Liao, Sophia Hy" uniqKey="Liao S" first="Sophia Hy" last="Liao">Sophia Hy Liao</name><affiliation><nlm:aff id="aff1"><institution>Gene Therapy Research Unit of the Children's Medical Research Institute and The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Dane, Allison P" sort="Dane, Allison P" uniqKey="Dane A" first="Allison P" last="Dane">Allison P. Dane</name><affiliation><nlm:aff id="aff1"><institution>Gene Therapy Research Unit of the Children's Medical Research Institute and The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Hu, Min" sort="Hu, Min" uniqKey="Hu M" first="Min" last="Hu">Min Hu</name><affiliation><nlm:aff id="aff2"><institution>Centre for Kidney Research of The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Hyman, Jessica" sort="Hyman, Jessica" uniqKey="Hyman J" first="Jessica" last="Hyman">Jessica Hyman</name><affiliation><nlm:aff id="aff3"><institution>Oncology Research Unit of The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Finnie, John W" sort="Finnie, John W" uniqKey="Finnie J" first="John W" last="Finnie">John W. Finnie</name><affiliation><nlm:aff id="aff4"><institution>Institute of Medical and Veterinary Science</institution> Adelaide, South Australia,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Zheng, Maolin" sort="Zheng, Maolin" uniqKey="Zheng M" first="Maolin" last="Zheng">Maolin Zheng</name><affiliation><nlm:aff id="aff1"><institution>Gene Therapy Research Unit of the Children's Medical Research Institute and The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Cavazzana Calvo, Marina" sort="Cavazzana Calvo, Marina" uniqKey="Cavazzana Calvo M" first="Marina" last="Cavazzana-Calvo">Marina Cavazzana-Calvo</name><affiliation><nlm:aff id="aff5"><institution>Paediatric Immunology and Haematology Unit, Hôpital Necker-Enfants Malades</institution> Paris,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Alexander, Stephen I" sort="Alexander, Stephen I" uniqKey="Alexander S" first="Stephen I" last="Alexander">Stephen I. Alexander</name><affiliation><nlm:aff id="aff2"><institution>Centre for Kidney Research of The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Thrasher, Adrian J" sort="Thrasher, Adrian J" uniqKey="Thrasher A" first="Adrian J" last="Thrasher">Adrian J. Thrasher</name><affiliation><nlm:aff id="aff6"><institution>Institute of Child Health, Great Ormond Street Hospital</institution> London,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Alexander, Ian E" sort="Alexander, Ian E" uniqKey="Alexander I" first="Ian E" last="Alexander">Ian E. Alexander</name><affiliation><nlm:aff id="aff1"><institution>Gene Therapy Research Unit of the Children's Medical Research Institute and The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff7"><institution>Discipline of Paediatrics and Child Health, The University of Sydney</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff></affiliation></author></analytic><series><title level="j">Molecular Therapy</title><idno type="ISSN">1525-0016</idno><idno type="eISSN">1525-0024</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The development of leukemia as a consequence of vector-mediated genotoxicity in gene therapy trials for X-linked severe combined immunodeficiency (SCID-X1) has prompted substantial research effort into the design and safety testing of integrating vectors. An important element of vector design is the selection and evaluation of promoter-enhancer elements with sufficient strength to drive reliable immune reconstitution, but minimal propensity for enhancer-mediated insertional mutagenesis. In this study, we set out to explore the effect of promoter-enhancer selection on the efficacy and safety of human immunodeficiency virus-1-derived lentiviral vectors in γc-deficient mice. We observed incomplete or absent T- and B-cell development in mice transplanted with progenitors expressing γc from the phosphoglycerate kinase (PGK) and Wiscott–Aldrich syndrome (WAS) promoters, respectively. In contrast, functional T- and B-cell compartments were restored in mice receiving an equivalent vector containing the elongation factor-1-α (EF1α) promoter; however, 4 of 14 mice reconstituted with this vector subsequently developed lymphoma. Extensive analyses failed to implicate insertional mutagenesis or γc overexpression as the underlying mechanism. These findings highlight the need for detailed mechanistic analysis of tumor readouts in preclinical animal models assessing vector safety, and suggest the existence of other ill-defined risk factors for oncogenesis, including replicative stress, in gene therapy protocols targeting the hematopoietic compartment.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-comment> Original-type: oa</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Mol Ther</journal-id><journal-title>Molecular Therapy</journal-title><issn pub-type="ppub">1525-0016</issn><issn pub-type="epub">1525-0024</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">20354504</article-id><article-id pub-id-type="pmc">2890120</article-id><article-id pub-id-type="pii">mt201050</article-id><article-id pub-id-type="doi">10.1038/mt.2010.50</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Articles</subject><subj-group><subject>Vector Toxicology, Immunogenicity and Safety</subject></subj-group></subj-group></article-categories><title-group><article-title>Lymphomagenesis in SCID-X1 Mice Following Lentivirus-mediated Phenotype Correction Independent of Insertional Mutagenesis and γc Overexpression</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Ginn</surname><given-names>Samantha L</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Liao</surname><given-names>Sophia HY</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Dane</surname><given-names>Allison P</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Hu</surname><given-names>Min</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Hyman</surname><given-names>Jessica</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Finnie</surname><given-names>John W</given-names></name><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Zheng</surname><given-names>Maolin</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Cavazzana-Calvo</surname><given-names>Marina</given-names></name><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Alexander</surname><given-names>Stephen I</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Thrasher</surname><given-names>Adrian J</given-names></name><xref ref-type="aff" rid="aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Alexander</surname><given-names>Ian E</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff7">7</xref></contrib></contrib-group><aff id="aff1"><label>1</label><institution>Gene Therapy Research Unit of the Children's Medical Research Institute and The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></aff><aff id="aff2"><label>2</label><institution>Centre for Kidney Research of The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></aff><aff id="aff3"><label>3</label><institution>Oncology Research Unit of The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></aff><aff id="aff4"><label>4</label><institution>Institute of Medical and Veterinary Science</institution> Adelaide, South Australia,<country>Australia</country></aff><aff id="aff5"><label>5</label><institution>Paediatric Immunology and Haematology Unit, Hôpital Necker-Enfants Malades</institution> Paris,<country>France</country></aff><aff id="aff6"><label>6</label><institution>Institute of Child Health, Great Ormond Street Hospital</institution> London,<country>UK</country></aff><aff id="aff7"><label>7</label><institution>Discipline of Paediatrics and Child Health, The University of Sydney</institution> Westmead, New South Wales,<country>Australia</country></aff><author-notes><corresp id="caf1"><label>*</label>Author for correspondence: <email xlink:href="mailto:iana@chw.edu.au">iana@chw.edu.au</email></corresp></author-notes><pub-date pub-type="epub"><day>30</day><month>03</month><year>2010</year></pub-date><pub-date pub-type="collection"><day>03</day><month>05</month><year>2010</year></pub-date><pub-date pub-type="ppub"><month>05</month><year>2010</year></pub-date><volume>18</volume><issue>5</issue><fpage>965</fpage><lpage>976</lpage><history><date date-type="received"><day>04</day><month>01</month><year>2010</year></date><date date-type="accepted"><day>02</day><month>03</month><year>2010</year></date></history><copyright-statement>Copyright 2010, The American Society of Gene & Cell Therapy</copyright-statement><copyright-year>2010</copyright-year><permissions><copyright-holder>The American Society of Gene & Cell Therapy</copyright-holder></permissions><abstract><p>The development of leukemia as a consequence of vector-mediated genotoxicity in gene therapy trials for X-linked severe combined immunodeficiency (SCID-X1) has prompted substantial research effort into the design and safety testing of integrating vectors. An important element of vector design is the selection and evaluation of promoter-enhancer elements with sufficient strength to drive reliable immune reconstitution, but minimal propensity for enhancer-mediated insertional mutagenesis. In this study, we set out to explore the effect of promoter-enhancer selection on the efficacy and safety of human immunodeficiency virus-1-derived lentiviral vectors in γc-deficient mice. We observed incomplete or absent T- and B-cell development in mice transplanted with progenitors expressing γc from the phosphoglycerate kinase (PGK) and Wiscott–Aldrich syndrome (WAS) promoters, respectively. In contrast, functional T- and B-cell compartments were restored in mice receiving an equivalent vector containing the elongation factor-1-α (EF1α) promoter; however, 4 of 14 mice reconstituted with this vector subsequently developed lymphoma. Extensive analyses failed to implicate insertional mutagenesis or γc overexpression as the underlying mechanism. These findings highlight the need for detailed mechanistic analysis of tumor readouts in preclinical animal models assessing vector safety, and suggest the existence of other ill-defined risk factors for oncogenesis, including replicative stress, in gene therapy protocols targeting the hematopoietic compartment.</p></abstract></article-meta></front><floats-wrap><fig id="fig1"><label><bold>Figure 1</bold></label><caption><p><bold>Lentiviral vector constructs used in this study.</bold> Vectors contained the promoter elements from either the 1,177 base-pair (bp) human elongation factor-1-α (EF1α), 516 bp human phosphoglycerate kinase (PGK), or 481 bp human Wiskott–Aldrich syndrome protein (WAS) genes to drive expression of the human γc cDNA. ψ, packaging and dimerization signal; GA, fragment of the HIV-1 <italic>gag</italic> gene; cPPT, central polypurine tract; RRE, Rev responsive element; RSV, Rous sarcoma virus hybrid promoter; SD/SA, splice-donor and spice-acceptor sites; WPRE, woodchuck hepatitis virus post-transcriptional regulatory element. The locations of unique and rare restriction endonuclease sites are indicated.</p></caption><graphic mime-subtype="eps" xlink:href="mt201050f1"></graphic></fig><fig id="fig2"><label><bold>Figure 2</bold></label><caption><p><bold>Restoration of lymphocyte populations following lentiviral vector–mediated gene transfer.</bold> (<bold>a</bold>) Splenocytes from transplant recipients were examined by flow cytometry using antibodies against murine B220, CD3, CD4, CD8, IgM, and NK1.1. (<bold>b</bold>) Thymopoiesis in transplant recipients receiving vector-treated progenitors was examined by flow cytometry using antibodies against CD3, CD4, and CD8. (<bold>c</bold>) Small intestinal samples were stained for CD3 and revealed intraepithelial lymphocyte development in wild-type mice and recipient mice following gene therapy. Bar = 100 µm.</p></caption><graphic mime-subtype="eps" xlink:href="mt201050f2"></graphic></fig><fig id="fig3"><label><bold>Figure 3</bold></label><caption><p><bold>Restoration of immune function following lentiviral vector–mediated gene transfer.</bold> (<bold>a</bold>) Splenocytes from transplant recipients or wild-type mice were stimulated under conditions to promote T-cell proliferation. Proliferating cells were evaluated by the incorporation of [3H] thymidine and expressed as the ratio of counts obtained for stimulated to unstimulated cells. Gray bars, conA alone; white bars, IL-2 alone; black bars, conA and IL-2. (<bold>b</bold>) Humoral immune responses, indicated by serum IgG, IgG1, and IgG2a levels, were examined in mice transplanted with vector-treated C57Bl/6 or IL2RG<sup>−/−</sup> progenitors, and compared to γc<sup>−/−</sup>Rag2<sup>−/−</sup>c5<sup>−/−</sup> mice transplanted with untransduced IL2RG<sup>−/−</sup> cells. Histograms represent the mean value for each group (<italic>n</italic> = 4) with error bars representing the standard error of the mean. *<italic>P</italic> < 0.05, **<italic>P</italic> < 0.01, ***<italic>P</italic> < 0.0001 (Wilcoxon rank-sum test). EF1α, elongation factor-1-α OD, optical density; PGK, phosphoglycerate kinase; WAS, Wiskott–Aldrich syndrome.</p></caption><graphic mime-subtype="eps" xlink:href="mt201050f3"></graphic></fig><fig id="fig4"><label><bold>Figure 4</bold></label><caption><p><bold>Analysis of T-cell receptor Vβ repertoire and CDR3 spectratyping in splenocytes from mice following lentiviral vector–mediated gene transfer.</bold> (<bold>a</bold>) Splenocytes were isolated from mice between 6 and 18 months post-transplantation, and V<sub>β</sub> repertoire analysis was performed by quantitative RT-PCR. The percentage of each V<sub>β</sub> family is indicated with results representing the mean of triplicate values for each group (<italic>n</italic> = 3) with error bars representing the SEM. Gray bars, C57Bl/6 control group; black bars, EF1α-γc treatment group. (<bold>b</bold>) CDR3 spectratypes of TCRV<sub>β</sub> 12-1, 13-1, 13-2, 16, and 20 families in reconstituted mice receiving either C57Bl/6 control or IL2RG<sup>−/−</sup> progenitor cells treated with the EF1α-EGFP or EF1α-γc vectors (m233 and m26, respectively). Normal Gaussian distribution (6–11 peaks each separated by three nucleotides) was observed for TCRV<sub>β</sub> 12-1, 13-1, 13-2, 16, and 20 in m223 and TCRV<sub>β</sub> 12-1, 13-1, 13-2, and 16 in m26. Restricted CDR3 spectratyping of TCRV<sub>β</sub> 16 in m21 (C57Bl/6 control progenitor cells treated with the EF1α-EGFP vector) and TCRV<sub>β</sub> 20 in m26 (IL2RG<sup>−/−</sup> progenitor cells treated with the EF1α-γc vector) was observed. EF1α, elongation factor-1-α TRBV, T-cell receptor V<sub>β</sub>.</p></caption><graphic mime-subtype="eps" xlink:href="mt201050f4"></graphic></fig><fig id="fig5"><label><bold>Figure 5</bold></label><caption><p><bold>Phenotypic characterization of lymphomas.</bold> (<bold>a</bold>) Kaplan–Meier survival analysis at 1 year post-transplantation. The percent lymphoma-free survival was significantly higher (<italic>P</italic> = 0.0134) for mice receiving C57Bl/6 progenitors treated with the EF1α-EGFP vector (<italic>n</italic> = 19) when compared to mice receiving EF1α-γc vector-treated IL2RG<sup>−/−</sup> cells (<italic>n</italic> = 14). (<bold>b</bold>) Malignant blasts, isolated from primary animals, were stained with antibodies against murine CD3, CD4, CD8, and B220, and analyzed by flow cytometry. (<bold>c</bold>) Hematoxylin and eosin staining revealed effacement of much of the normal splenic architecture by proliferating lymphoblastic cells (top panel) with marked hepatic infiltration by metastatic lymphoblasts (bottom panel) in mice from the EF1α-γc treatment group. Bar = 100 µm. EF1α, elongation factor-1-α.</p></caption><graphic mime-subtype="eps" xlink:href="mt201050f5"></graphic></fig><table-wrap id="tbl1" position="float"><label><bold>Table 1</bold></label><caption><p content-type="table-title"><bold>Peripheral lymphocyte reconstitution following transplantation</bold></p></caption><graphic xlink:href="mt201050t1"></graphic></table-wrap><table-wrap id="tbl2" position="float"><label><bold>Table 2</bold></label><caption><p content-type="table-title"><bold>Lymphocyte subset determination in the spleens of mice following transplantation</bold></p></caption><graphic xlink:href="mt201050t2"></graphic></table-wrap><table-wrap id="tbl3" position="float"><label><bold>Table 3</bold></label><caption><p content-type="table-title"><bold>Vector integration sites recovered from malignant clones</bold></p></caption><graphic xlink:href="mt201050t3"></graphic></table-wrap></floats-wrap></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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