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  • Original Article
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Selective ablation of the YxxM motif of IL-7Rα suppresses lymphomagenesis but maintains lymphocyte development

Abstract

Tumor progression is a multiple step process in which, in addition to oncogenic mutation, other supporting factors can contribute to transformation. The role these factors have in cancer is an open question. Using the Eμ-myc model of B-cell transformation, we evaluated the contribution of the cytokine interleukin-7 (IL-7) in supporting lymphomagenesis. We have previously shown that disruption of the Y449xxM motif of the IL-7 receptor alpha (IL-7Rα) in a knock-in mouse model (IL-7Rα449F) has minor effects on lymphocyte production, but interferes with the activation of survival effectors. To address the hypothesis that targeted signal ablation would selectively affect lymphocyte transformation, IL-7Rα449F mice were crossed with two lymphomagenesis models, transgenic (Tg) IL-7 and Eμ-myc mice. We found that the loss of IL-7Rα Y449 signaling prevented Tg IL-7-mediated T- and B-lymphocyte transformation and decreased the development of Eμ-myc-induced B-cell tumors. We showed that the IL-7Rα449F mutation prevented increased survival of Tg IL-7 CD8 T cells, and decreased viability of bone marrow progenitor B cells, as well as Eμ-myc-induced proliferation. This study shows that IL-7Rα Y449 is important for lymphocyte transformation, and that unlike deficiencies in pre-B cell receptor signaling, Myc overexpression cannot compensate for the loss of IL-7Rα signals in early B-cell development.

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References

  • Abraham N, Ma MC, Snow JW, Miners MJ, Herndier BG, Goldsmith MA . (2005). Haploinsufficiency identifies STAT5 as a modifier of IL-7-induced lymphomas. Oncogene 24: 5252–5257.

    Article  CAS  PubMed  Google Scholar 

  • Adams JM, Harris AW, Pinkert CA, Corcoran LM, Alexander WS, Cory S et al. (1985). The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318: 533–538.

    Article  CAS  PubMed  Google Scholar 

  • Adams JM, Harris AW, Strasser A, Ogilvy S, Cory S . (1999). Transgenic models of lymphoid neoplasia and development of a pan-hematopoietic vector. Oncogene 18: 5268–5277.

    Article  CAS  PubMed  Google Scholar 

  • Barata JT, Cardoso AA, Nadler LM, Boussiotis VA . (2001). Interleukin-7 promotes survival and cell cycle progression of T-cell acute lymphoblastic leukemia cells by down-regulating the cyclin-dependent kinase inhibitor p27(kip1). Blood 98: 1524–1531.

    Article  CAS  PubMed  Google Scholar 

  • Barata JT, Silva A, Brandao JG, Nadler LM, Cardoso AA, Boussiotis VA . (2004). Activation of PI3K is indispensable for interleukin 7-mediated viability, proliferation, glucose use, and growth of T cell acute lymphoblastic leukemia cells. J Exp Med 200: 659–669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Canadian Cancer Society/National Cancer Institute of Canada (2008). Canadian Cancer Statistics. Canadian Cancer Society/National Cancer Institute of Canada: Toronto, Canada, ISSN0835-2976.

  • Cattaruzza L, Gloghini A, Olivo K, Di Francia R, Lorenzon D, De Filippi R et al. (2009). Functional coexpression of interleukin (IL)-7 and its receptor (IL-7R) on Hodgkin and Reed-Sternberg cells: involvement of IL-7 in tumor cell growth and microenvironmental interactions of Hodgkin's lymphoma. Int J Cancer 125: 1092–1101.

    Article  CAS  PubMed  Google Scholar 

  • Duthie KA, Osborne LC, Foster LJ, Abraham N . (2007). Proteomic analysis of IL-7 induced signaling effectors show selective changes in IL-7Ralpha 449F knock-in T cell progenitors. Mol Cell Proteomics 6: 1700–1710.

    Article  CAS  PubMed  Google Scholar 

  • Eischen CM, Packham G, Nip J, Fee BE, Hiebert SW, Zambetti GP et al. (2001a). Bcl-2 is an apoptotic target suppressed by both c-myc and E2F-1. Oncogene 20: 6983–6993.

    Article  CAS  PubMed  Google Scholar 

  • Eischen CM, Weber JD, Roussel MF, Sherr CJ, Cleveland JL . (1999). Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in myc-induced lymphomagenesis. Genes Dev 13: 2658–2669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eischen CM, Woo D, Roussel MF, Cleveland JL . (2001b). Apoptosis triggered by myc-induced suppression of bcl-XL or bcl-2 is bypassed during lymphomagenesis. Mol Cell Biol 21: 5063–5070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • El Kassar N, Lucas PJ, Klug DB, Zamisch M, Merchant M, Bare CV et al. (2004). A dose effect of IL-7 on thymocyte development. Blood 104: 1419–1427.

    Article  CAS  PubMed  Google Scholar 

  • Fleming HE, Paige CJ . (2002). Cooperation between IL-7 and the pre-B cell receptor: a key to B cell selection. Semin Immunol 14: 423–430.

    Article  CAS  PubMed  Google Scholar 

  • Foss HD, Hummel M, Gottstein S, Ziemann K, Falini B, Herbst H et al. (1995). Frequent expression of IL-7 gene transcripts in tumor cells of classical Hodgkin's disease. Am J Pathol 146: 33–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Habib T, Park H, Tsang M, de Alboran IM, Nicks A, Wilson L et al. (2007). Myc stimulates B lymphocyte differentiation and amplifies calcium signaling. J Cell Biol 179: 717–731.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer SJ . (1993). Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 75: 241–251.

    Article  CAS  PubMed  Google Scholar 

  • Juarez J, Baraz R, Gaundar S, Bradstock K, Bendall L . (2007). Interaction of interleukin-7 and interleukin-3 with the CXCL12-induced proliferation of B-cell progenitor acute lymphoblastic leukemia. Haematologica 92: 450–459.

    Article  CAS  PubMed  Google Scholar 

  • Keller U, Nilsson JA, Maclean KH, Old JB, Cleveland JL . (2005). Nfkb 1 is dispensable for myc-induced lymphomagenesis. Oncogene 24: 6231–6240.

    Article  CAS  PubMed  Google Scholar 

  • Kelly PN, Puthalakath H, Adams JM, Strasser A . (2007). Endogenous bcl-2 is not required for the development of emu-myc-induced B-cell lymphoma. Blood 109: 4907–4913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kotani A, Kakazu N, Tsuruyama T, Okazaki IM, Muramatsu M, Kinoshita K et al. (2007). Activation-induced cytidine deaminase (AID) promotes B cell lymphomagenesis in emu-cmyc transgenic mice. Proc Natl Acad Sci USA 104: 1616–1620.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kovanen PE, Leonard WJ . (2004). Cytokines and immunodeficiency diseases: critical roles of the gamma(c)-dependent cytokines interleukins 2, 4, 7, 9, 15, and 21, and their signaling pathways. Immunol Rev 202: 67–83.

    Article  CAS  PubMed  Google Scholar 

  • Lali FV, Crawley J, McCulloch DA, Foxwell BM . (2004). A late, prolonged activation of the phosphatidylinositol 3-kinase pathway is required for T cell proliferation. J Immunol 172: 3527–3534.

    Article  CAS  PubMed  Google Scholar 

  • Langdon WY, Harris AW, Cory S, Adams JM . (1986). The c-myc oncogene perturbs B lymphocyte development in E-mu-myc transgenic mice. Cell 47: 11–18.

    Article  CAS  PubMed  Google Scholar 

  • Long BW, Witte PL, Abraham GN, Gregory SA, Plate JM . (1995). Apoptosis and interleukin 7 gene expression in chronic B-lymphocytic leukemia cells. Proc Natl Acad Sci USA 92: 1416–1420.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marshall AJ, Fleming HE, Wu GE, Paige CJ . (1998). Modulation of the IL-7 dose-response threshold during pro-B cell differentiation is dependent on pre-B cell receptor expression. J Immunol 161: 6038–6045.

    CAS  PubMed  Google Scholar 

  • Nepal RM, Zaheen A, Basit W, Li L, Berger SA, Martin A . (2008). AID and RAG1 do not contribute to lymphomagenesis in E mu c-myc transgenic mice. Oncogene 27: 4752–4756.

    Article  CAS  PubMed  Google Scholar 

  • Nilsson LM, Keller UB, Yang C, Nilsson JA, Cleveland JL, Roussel MF . (2007). Ink4c is dispensable for tumor suppression in myc-induced B-cell lymphomagenesis. Oncogene 26: 2833–2839.

    Article  CAS  PubMed  Google Scholar 

  • Osborne LC, Dhanji S, Snow JW, Priatel JJ, Ma MC, Miners MJ et al. (2007). Impaired CD8 T cell memory and CD4 T cell primary responses in IL-7R alpha mutant mice. J Exp Med 204: 619–631.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pallard C, Stegmann AP, van Kleffens T, Smart F, Venkitaraman A, Spits H . (1999). Distinct roles of the phosphatidylinositol 3-kinase and STAT5 pathways in IL-7-mediated development of human thymocyte precursors. Immunity 10: 525–535.

    Article  CAS  PubMed  Google Scholar 

  • Peschon JJ, Morrissey PJ, Grabstein KH, Ramsdell FJ, Maraskovsky E, Gliniak BC et al. (1994). Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med 180: 1955–1960.

    Article  CAS  PubMed  Google Scholar 

  • Rich BE, Campos TJ, Tepper RI, Moreadith RW, Leder P . (1993). Cutaneous lymphoproliferation and lymphomas in interleukin 7 transgenic mice. J Exp Med 177: 305–316.

    Article  CAS  PubMed  Google Scholar 

  • Sasson SC, Smith S, Seddiki N, Zaunders JJ, Bryant A, Koelsch KK et al. (2010). IL-7 receptor is expressed on adult pre-B-cell acute lymphoblastic leukemia and other B-cell derived neoplasms and correlates with expression of proliferation and survival markers. Cytokine 50: 58–68.

    Article  CAS  PubMed  Google Scholar 

  • Scott CL, Schuler M, Marsden VS, Egle A, Pellegrini M, Nesic D et al. (2004). Apaf-1 and caspase-9 do not act as tumor suppressors in myc-induced lymphomagenesis or mouse embryo fibroblast transformation. J Cell Biol 164: 89–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scupoli MT, Perbellini O, Krampera M, Vinante F, Cioffi F, Pizzolo G . (2007). Interleukin 7 requirement for survival of T-cell acute lymphoblastic leukemia and human thymocytes on bone marrow stroma. Haematologica 92: 264–266.

    Article  PubMed  Google Scholar 

  • Touw I, Pouwels K, van Agthoven T, van Gurp R, Budel L, Hoogerbrugge H et al. (1990). Interleukin-7 is a growth factor of precursor B and T acute lymphoblastic leukemia. Blood 75: 2097–2101.

    CAS  PubMed  Google Scholar 

  • von Freeden-Jeffry U, Vieira P, Lucian LA, McNeil T, Burdach SE, Murray R . (1995). Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J Exp Med 181: 1519–1526.

    Article  CAS  PubMed  Google Scholar 

  • Wei C, Zeff R, Goldschneider I . (2000). Murine pro-B cells require IL-7 and its receptor complex to up-regulate IL-7R alpha, terminal deoxynucleotidyltransferase, and c mu expression. J Immunol 164: 1961–1970.

    Article  CAS  PubMed  Google Scholar 

  • Wen R, Chen Y, Bai L, Fu G, Schuman J, Dai X et al. (2006). Essential role of phospholipase C gamma 2 in early B-cell development and myc-mediated lymphomagenesis. Mol Cell Biol 26: 9364–9376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wofford JA, Wieman HL, Jacobs SR, Zhao Y, Rathmell JC . (2008). IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of akt to support T-cell survival. Blood 111: 2101–2111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yasuda T, Sanjo H, Pages G, Kawano Y, Karasuyama H, Pouyssegur J et al. (2008). Erk kinases link pre-B cell receptor signaling to transcriptional events required for early B cell expansion. Immunity 28: 499–508.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr Robert Kay, Martin Richer and Caylib Durand for critical reading of the paper; Jill Miners, Eric Ma Asavee and Rachel Kim for animal colony maintenance and genotyping; Dr Sarah Gaffen for technical assistance; Nadia Gale and staff at the Centre for Translational and Applied Genomics; Dr Christine Eischen for providing C57BL/6 Eμ-myc mice; Dr Bart Vanhaesebroeck for providing C57BL/6 p110δD910A mice; Dr Philippa Marrack for providing anti-Bim-producing Ham151 cells and the Wesbrook Animal Unit staff for animal husbandry. This work is supported by the Canadian Institutes for Health Research (CIHR) (MOP-67005 and MOP-84532 to N Abraham). LCO was supported by studentships from the Michael Smith Foundation for Health Research (MSFHR), the Natural Sciences and Engineering Research Council (NSERC) and the CIHR/MSFHR Strategic Training Program in Transplantation Research. KAD was supported by an NSERC Postgraduate scholarship. NA holds CIHR New Investigator and MSFHR Career Investigator awards.

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Correspondence to N Abraham.

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Osborne, L., Duthie, K., Seo, J. et al. Selective ablation of the YxxM motif of IL-7Rα suppresses lymphomagenesis but maintains lymphocyte development. Oncogene 29, 3854–3864 (2010). https://doi.org/10.1038/onc.2010.133

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