Mature T-cell lymphomagenesis induced by retroviral insertional activation of Janus kinase 1
Tim Heinrich, Benjamin Rengstl, Alexander Muik, Mina Petkova, Frederike Schmid, Robin Wistinghausen, Kathrin Warner, Giuliano Crispatzu, Martin-Leo Hansmann, Marco Herling, Dorothee von Laer, Sebastian Newrzela, Tim Heinrich, Benjamin Rengstl, Alexander Muik, Mina Petkova, Frederike Schmid, Robin Wistinghausen, Kathrin Warner, Giuliano Crispatzu, Martin-Leo Hansmann, Marco Herling, Dorothee von Laer, Sebastian Newrzela
Abstract
Retroviral vectors (RVs) are powerful tools in clinical gene therapy. However, stable genomic integration of RVs can be oncogenic, as reported in several animal models and in clinical trials. Previously, we observed that T-cell receptor (TCR) polyclonal mature T cells are resistant to transformation after gammaretroviral transfer of (proto-)oncogenes, whereas TCR-oligoclonal T cells were transformable in the same setting. Here, we describe the induction of a mature T-cell lymphoma (MTCL) in TCR-oligoclonal OT-I transgenic T cells, transduced with an enhanced green fluorescent protein (EGFP)-encoding gammaretroviral vector. The tumor cells were of a mature T-cell phenotype and serially transplantable. Integration site analysis revealed a proviral hit in Janus kinase 1 (Jak1), which resulted in Jak1 overexpression and Jak/STAT-pathway activation, particularly via signal transducer and activator of transcription 3 (STAT3). Specific inhibition of Jak1 markedly delayed tumor growth. A systematic meta-analysis of available gene expression data on human mature T-cell lymphomas/leukemias confirmed the relevance of Jak/STAT overexpression in sporadic human T-cell tumorigenesis. To our knowledge, this is the first study to describe RV-associated insertional mutagenesis in mature T cells.
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References
- Wu X, Li Y, Crise B, Burgess SM. Transcription start regions in the human genome are favored targets for MLV integration. Science. 2003;300:1749–1751.
- Laufs S, Nagy KZ, Giordano FA, Hotz-Wagenblatt A, Zeller WJ, Fruehauf S. Insertion of retroviral vectors in NOD/SCID repopulating human peripheral blood progenitor cells occurs preferentially in the vicinity of transcription start regions and in introns. Mol Ther. 2004;10:874–881.
- Bushman F, Lewinski M, Ciuffi A, Barr S, Leipzig J, Hannenhalli S, et al. Genome-wide analysis of retroviral DNA integration. Nat Rev Microbiol. 2005;3:848–858.
- Staal FJ, Pike-Overzet K, Ng YY, van Dongen JJ. Sola dosis facit venenum. Leukemia in gene therapy trials: a question of vectors, inserts and dosage. Leukemia. 2008;22:1849–1852.
- Li Z, Düllmann J, Schiedlmeier B, Schmidt M, von Kalle C, Meyer J, et al. Murine leukemia induced by retroviral gene marking. Science. 2002;296:497.
- Hacein-Bey-Abina S, Garrigue A, Wang GP, Soulier J, Lim A, Morillon E, et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest. 2008;118:3132–3142.
- Howe SJ, Mansour MR, Schwarzwaelder K, Bartholomae C, Hubank M, Kempski H, et al. Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. J Clin Invest. 2008;118:3143–3150.
- Ott MG, Schmidt M, Schwarzwaelder K, Stein S, Siler U, Koehl U, et al. Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat Med. 2006;12:401–409.
- Stein S, Ott MG, Schultze-Strasser S, Jauch A, Burwinkel B, Kinner A, et al. Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nat Med. 2010;16:198–204.
- Avedillo Díez I, Zychlinski D, Coci EG, Galla M, Modlich U, Dewey RA, et al. Development of novel efficient SIN vectors with improved safety features for Wiskott-Aldrich syndrome stem cell based gene therapy. Mol Pharm. 2011;8:1525–1537.
- Bonini C, Grez M, Traversari C, Ciceri F, Marktel S, Ferrari G, et al. Safety of retroviral gene marking with a truncated NGF receptor. Nat Med. 2003;9:367–369.
- Scholler J, Brady TL, Binder-Scholl G, Hwang WT, Plesa G, Hege KM, et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci Transl Med. 2012;4:132ra53.
- Recchia A, Bonini C, Magnani Z, Urbinati F, Sartori D, Muraro S, et al. Retroviral vector integration deregulates gene expression but has no consequence on the biology and function of transplanted T cells. Proc Natl Acad Sci USA. 2006;103:1457–1462.
- Surh CD, Sprent J. Regulation of mature T cell homeostasis. Semin Immunol. 2005;17:183–191.
- Hays EF, Bristol GC, McDougall S, Klotz JL, Kronenberg M. Development of lymphoma in the thymus of AKR mice treated with the lymphomagenic virus SL 3-3. Cancer Res. 1989;49:4225–4230.
- Newrzela S, Cornils K, Li Z, Baum C, Brugman MH, Hartmann M, et al. Resistance of mature T cells to oncogene transformation. Blood. 2008;112:2278–2286.
- Newrzela S, Cornils K, Heinrich T, Schläger J, Yi JH, Lysenko O, et al. Retroviral insertional mutagenesis can contribute to immortalization of mature T lymphocytes. Mol Med. 2011;17:1223–1232.
- Newrzela S, Al-Ghaili N, Heinrich T, Petkova M, Hartmann S, Rengstl B, et al. T-cell receptor diversity prevents T-cell lymphoma development. Leukemia. 2012;26:2499–2507.
- Akagi K, Suzuki T, Stephens RM, Jenkins NA, Copeland NG. RTCGD: retroviral tagged cancer gene database. Nucleic Acids Res. 2004;32 Database issue:D523–D527.
- Quintás-Cardama A, Vaddi K, Liu P, Manshouri T, Li J, Scherle PA, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010;115:3109–3117.
- Meyer J, Rhein M, Schiedlmeier B, Kustikova O, Rudolph C, Kamino K, et al. Remarkable leukemogenic potency and quality of a constitutively active neurotrophin receptor, deltaTrkA. Leukemia. 2007;21:2171–2180.
- Iqbal J, Weisenburger DD, Chowdhury A, Tsai MY, Srivastava G, Greiner TC, International Peripheral T-cell Lymphoma Project et al. Natural killer cell lymphoma shares strikingly similar molecular features with a group of non-hepatosplenic ?d T-cell lymphoma and is highly sensitive to a novel aurora kinase A inhibitor in vitro. Leukemia. 2011;25:348–358.
- Iqbal J, Weisenburger DD, Greiner TC, Vose JM, McKeithan T, Kucuk C, International Peripheral T-Cell Lymphoma Project et al. Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma. Blood. 2010;115:1026–1036.
- Piccaluga PP, Agostinelli C, Califano A, Rossi M, Basso K, Zupo S, et al. Gene expression analysis of peripheral T cell lymphoma, unspecified, reveals distinct profiles and new potential therapeutic targets. J Clin Invest. 2007;117:823–834.
- Travert M, Huang Y, de Leval L, Martin-Garcia N, Delfau-Larue MH, Berger F, et al. Molecular features of hepatosplenic T-cell lymphoma unravels potential novel therapeutic targets. Blood. 2012;119:5795–5806.
- van Doorn R, van Kester MS, Dijkman R, Vermeer MH, Mulder AA, Szuhai K, et al. Oncogenomic analysis of mycosis fungoides reveals major differences with Sezary syndrome. Blood. 2009;113:127–136.
- de Leval L, Rickman DS, Thielen C, Reynies Ad, Huang YL, Delsol G, et al. The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells. Blood. 2007;109:4952–4963.
- Dürig J, Bug S, Klein-Hitpass L, Boes T, Jöns T, Martin-Subero JI, et al. Combined single nucleotide polymorphism-based genomic mapping and global gene expression profiling identifies novel chromosomal imbalances, mechanisms and candidate genes important in the pathogenesis of T-cell prolymphocytic leukemia with inv(14)(q11q32). Leukemia. 2007;21:2153–2163.
- Shin J, Monti S, Aires DJ, Duvic M, Golub T, Jones DA, et al. Lesional gene expression profiling in cutaneous T-cell lymphoma reveals natural clusters associated with disease outcome. Blood. 2007;110:3015–3027.
- Eckerle S, Brune V, Döring C, Tiacci E, Bohle V, Sundström C, et al. Gene expression profiling of isolated tumour cells from anaplastic large cell lymphomas: insights into its cellular origin, pathogenesis and relation to Hodgkin lymphoma. Leukemia. 2009;23:2129–2138.
- Lamant L, de Reyniès A, Duplantier MM, Rickman DS, Sabourdy F, Giuriato S, et al. Gene-expression profiling of systemic anaplastic large-cell lymphoma reveals differences based on ALK status and two distinct morphologic ALK+ subtypes. Blood. 2007;109:2156–2164.
- Deeks SG, Wagner B, Anton PA, Mitsuyasu RT, Scadden DT, Huang C, et al. A phase II randomized study of HIV-specific T-cell gene therapy in subjects with undetectable plasma viremia on combination antiretroviral therapy. Mol Ther. 2002;5:788–797.
- Mitsuyasu RT, Anton PA, Deeks SG, Scadden DT, Connick E, Downs MT, et al. Prolonged survival and tissue trafficking following adoptive transfer of CD4zeta gene-modified autologous CD4(+) and CD8(+) T cells in human immunodeficiency virus-infected subjects. Blood. 2000;96:785–793.
- Walker RE, Bechtel CM, Natarajan V, Baseler M, Hege KM, Metcalf JA, et al. Long-term in vivo survival of receptor-modified syngeneic T cells in patients with human immunodeficiency virus infection. Blood. 2000;96:467–474.
- Migone TS, Lin JX, Cereseto A, Mulloy JC, O'Shea JJ, Franchini G, et al. Constitutively activated Jak-STAT pathway in T cells transformed with HTLV-I. Science. 1995;269:79–81.
- Yu CL, Jove R, Burakoff SJ. Constitutive activation of the Janus kinase-STAT pathway in T lymphoma overexpressing the Lck protein tyrosine kinase. J Immunol. 1997;159:5206–5210.
- Flex E, Petrangeli V, Stella L, Chiaretti S, Hornakova T, Knoops L, et al. Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. J Exp Med. 2008;205:751–758.
- Zhang Q, Raghunath PN, Xue L, Majewski M, Carpentieri DF, Odum N, et al. Multilevel dysregulation of STAT3 activation in anaplastic lymphoma kinase-positive T/null-cell lymphoma. J Immunol. 2002;168:466–474.
- Khoury JD, Medeiros LJ, Rassidakis GZ, Yared MA, Tsioli P, Leventaki V, et al. Differential expression and clinical significance of tyrosine-phosphorylated STAT3 in ALK+ and ALK- anaplastic large cell lymphoma. Clin Cancer Res. 2003;9 10 Pt 1:3692–3699.
- Sommer VH, Clemmensen OJ, Nielsen O, Wasik M, Lovato P, Brender C, et al. In vivo activation of STAT3 in cutaneous T-cell lymphoma. Evidence for an antiapoptotic function of STAT3. Leukemia. 2004;18:1288–1295.
- Schambach A, Wodrich H, Hildinger M, Bohne J, Kräusslich HG, Baum C. Context dependence of different modules for posttranscriptional enhancement of gene expression from retroviral vectors. Mol Ther. 2000;2:435–445.
- Newrzela S, Gunda B, von Laer D. T cell culture for gammaretroviral transfer. Methods Mol Biol. 2009;506:71–82.
- Li LC, Dahiya R. MethPrimer: designing primers for methylation PCRs. Bioinformatics. 2002;18:1427–1431.
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