Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes

Abstract

The genomic region encoding the miR-17-92 microRNA (miRNA) cluster is often amplified in lymphoma and other cancers, and cancer cells carrying this amplification have higher expression of miRNA in this cluster. Retroviral expression of miR-17-92 accelerates c-Myc-induced lymphoma development, but precisely how higher expression of miR-17-92 promotes lymphomagenesis remains unclear. Here we generated mice with higher expression of miR-17-92 in lymphocytes. These mice developed lymphoproliferative disease and autoimmunity and died prematurely. Lymphocytes from these mice showed more proliferation and less activation-induced cell death. The miR-17-92 miRNA suppressed expression of the tumor suppressor PTEN and the proapoptotic protein Bim. This mechanism probably contributed to the lymphoproliferative disease and autoimmunity of miR-17-92-transgenic mice and contributes to lymphoma development in patients with amplifications of the miR-17-92 coding region.

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Figure 1: Expression of miR-17-92 miRNA.
Figure 2: The miR-17-92-transgenic mice develop hyperplasia of peripheral lymphoid tissues and have a shorter life span.
Figure 3: Effect of increased miR-17-92 expression on peripheral lymphocytes.
Figure 4: Autoimmunity in miR-17-92-transgenic mice.
Figure 5: Enhanced proliferation and survival of miR-17-92-transgenic lymphocytes.
Figure 6: Cytokine expression in miR-17-92-transgenic T cells.
Figure 7: The miR-17-92 miRNA molecules control the expression of PTEN and Bim protein.
Figure 8: Accumulation of antigen-experienced T cells and germinal center B cells in PTEN and Bim compound-heterozygous mice.

References

  1. 1

    Goodnow, C.C. Multistep pathogenesis of autoimmune disease. Cell 130, 25–35 (2007).

  2. 2

    Hanahan, D. & Weinberg, R.A. The hallmarks of cancer. Cell 100, 57–70 (2000).

  3. 3

    Di Cristofano, A., Pesce, B., Cordon-Cardo, C. & Pandolfi, P.P. Pten is essential for embryonic development and tumour suppression. Nat. Genet. 19, 348–355 (1998).

  4. 4

    Suzuki, A. et al. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr. Biol. 8, 1169–1178 (1998).

  5. 5

    Podsypanina, K. et al. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc. Natl. Acad. Sci. USA 96, 1563–1568 (1999).

  6. 6

    Suzuki, A. et al. T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity 14, 523–534 (2001).

  7. 7

    Bouillet, P. et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286, 1735–1738 (1999).

  8. 8

    Egle, A., Harris, A.W., Bouillet, P. & Cory, S. Bim is a suppressor of Myc-induced mouse B cell leukemia. Proc. Natl. Acad. Sci. USA 101, 6164–6169 (2004).

  9. 9

    Strasser, A. The role of BH3-only proteins in the immune system. Nat. Rev. Immunol. 5, 189–200 (2005).

  10. 10

    Strasser, A. & Bouillet, P. The control of apoptosis in lymphocyte selection. Immunol. Rev. 193, 82–92 (2003).

  11. 11

    Bouillet, P. et al. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415, 922–926 (2002).

  12. 12

    Di Cristofano, A. et al. Impaired Fas response and autoimmunity in Pten+/− mice. Science 285, 2122–2125 (1999).

  13. 13

    Bartel, D.P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).

  14. 14

    Chen, C.Z. & Lodish, H.F. MicroRNAs as regulators of mammalian hematopoiesis. Semin. Immunol. 17, 155–165 (2005).

  15. 15

    Mendell, J.T. MicroRNAs: critical regulators of development, cellular physiology and malignancy. Cell Cycle 4, 1179–1184 (2005).

  16. 16

    Calin, G.A. et al. MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proc. Natl. Acad. Sci. USA 101, 11755–11760 (2004).

  17. 17

    Calin, G.A. et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc. Natl. Acad. Sci. USA 101, 2999–3004 (2004).

  18. 18

    Lu, J. et al. MicroRNA expression profiles classify human cancers. Nature 435, 834–838 (2005).

  19. 19

    Ota, A. et al. Identification and characterization of a novel gene, C13orf25, as a target for 13q31-q32 amplification in malignant lymphoma. Cancer Res. 64, 3087–3095 (2004).

  20. 20

    Zhang, B., Pan, X., Cobb, G.P. & Anderson, T.A. microRNAs as oncogenes and tumor suppressors. Dev. Biol. 302, 1–12 (2007).

  21. 21

    Tagawa, H. & Seto, M. A microRNA cluster as a target of genomic amplification in malignant lymphoma. Leukemia 19, 2013–2016 (2005).

  22. 22

    He, L. et al. A microRNA polycistron as a potential human oncogene. Nature 435, 828–833 (2005).

  23. 23

    Tanzer, A. & Stadler, P.F. Molecular evolution of a microRNA cluster. J. Mol. Biol. 339, 327–335 (2004).

  24. 24

    de Boer, J. et al. Transgenic mice with hematopoietic and lymphoid specific expression of Cre. Eur. J. Immunol. 33, 314–325 (2003).

  25. 25

    Lee, Y. et al. The nuclear RNase III Drosha initiates microRNA processing. Nature 425, 415–419 (2003).

  26. 26

    Testi, R., Phillips, J.H. & Lanier, L.L. Leu 23 induction as an early marker of functional CD3/T cell antigen receptor triggering. Requirement for receptor cross-linking, prolonged elevation of intracellular [Ca++] and stimulation of protein kinase C. J. Immunol. 142, 1854–1860 (1989).

  27. 27

    Okkenhaug, K. et al. A point mutation in CD28 distinguishes proliferative signals from survival signals. Nat. Immunol. 2, 325–332 (2001).

  28. 28

    Pages, F. et al. Binding of phosphatidylinositol-3-OH kinase to CD28 is required for T-cell signalling. Nature 369, 327–329 (1994).

  29. 29

    Snapper, C.M. & Paul, W.E. Interferon-gamma and B cell stimulatory factor-1 reciprocally regulate Ig isotype production. Science 236, 944–947 (1987).

  30. 30

    Finkelman, F.D., Katona, I.M., Mosmann, T.R. & Coffman, R.L. IFN-γ regulates the isotypes of Ig secreted during in vivo humoral immune responses. J. Immunol. 140, 1022–1027 (1988).

  31. 31

    Snapper, C.M., Finkelman, F.D., Stefany, D., Conrad, D.H. & Paul, W.E. IL-4 induces co-expression of intrinsic membrane IgG1 and IgE by murine B cells stimulated with lipopolysaccharide. J. Immunol. 141, 489–498 (1988).

  32. 32

    Shparago, N. et al. IL-10 selectively regulates murine Ig isotype switching. Int. Immunol. 8, 781–790 (1996).

  33. 33

    Sosic, D., Richardson, J.A., Yu, K., Ornitz, D.M. & Olson, E.N. Twist regulates cytokine gene expression through a negative feedback loop that represses NF-κB activity. Cell 112, 169–180 (2003).

  34. 34

    Krek, A. et al. Combinatorial microRNA target predictions. Nat. Genet. 37, 495–500 (2005).

  35. 35

    Lewis, B.P., Shih, I.H., Jones-Rhoades, M.W., Bartel, D.P. & Burge, C.B. Prediction of mammalian microRNA targets. Cell 115, 787–798 (2003).

  36. 36

    Lewis, B.P., Burge, C.B. & Bartel, D.P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20 (2005).

  37. 37

    Koralov, S.B. et al. Dicer ablation affects antibody diversity and cell survival in the B lymphocyte lineage. Cell (in the press).

  38. 38

    Lindsley, R.C., Thomas, M., Srivastava, B. & Allman, D. Generation of peripheral B cells occurs via two spatially and temporally distinct pathways. Blood 109, 2521–2528 (2007).

  39. 39

    Vinuesa, C.G. et al. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435, 452–458 (2005).

  40. 40

    Grimson, A. et al. MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol. Cell 27, 91–105 (2007).

  41. 41

    Kertesz, M., Iovino, N., Unnerstall, U., Gaul, U. & Segal, E. The role of site accessibility in microRNA target recognition. Nat. Genet. 39, 1278–1284 (2007).

  42. 42

    Kedde, M. et al. RNA-binding protein Dnd1 inhibits microRNA access to target mRNA. Cell 131, 1273–1286 (2007).

  43. 43

    O'Donnell, K.A., Wentzel, E.A., Zeller, K.I., Dang, C.V. & Mendell, J.T. c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435, 839–843 (2005).

  44. 44

    Sylvestre, Y. et al. An E2F/miR-20a autoregulatory feedback loop. J. Biol. Chem. 282, 2135–2143 (2007).

  45. 45

    Yamasaki, L. et al. Tumor induction and tissue atrophy in mice lacking E2F–1. Cell 85, 537–548 (1996).

  46. 46

    Field, S.J. et al. E2F–1 functions in mice to promote apoptosis and suppress proliferation. Cell 85, 549–561 (1996).

  47. 47

    Murga, M. et al. Mutation of E2F2 in mice causes enhanced T lymphocyte proliferation, leading to the development of autoimmunity. Immunity 15, 959–970 (2001).

  48. 48

    Zhu, J.W. et al. E2F1 and E2F2 determine thresholds for antigen-induced T-cell proliferation and suppress tumorigenesis. Mol. Cell. Biol. 21, 8547–8564 (2001).

  49. 49

    Sasaki, Y. et al. Canonical NF-κB activity, dispensable for B cell development, replaces BAFF-receptor signals and promotes B cell proliferation upon activation. Immunity 24, 729–739 (2006).

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Acknowledgements

We thank D. Ghitza, C. Aristoff, M. Curnutte, A. Monti, A. Tetreault, A. Pellerin and A. Shahsafaei for technical assistance; A. Krek and N. Rajewsky for bioinformatics support; M.C. Carrol (Immune Disease Institute) for providing fluorescein isothiocyanate–conjugated rabbit antibody to human C3d complement; K. Otipoby for intellectual input; and all members of the Rajewsky lab for discussions. Supported by the National Institutes of Health (AI064345 to K.R.), the European Union (MUGEN; K.R.), the Cancer Research Institute (C.X.), the Joint Program in Hematology and Transfusion Medicine at Harvard Medical School (T32 training grant to C.X. and L.S.) and the Portuguese Foundation for Science and Technology (D.P.C).

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Correspondence to Klaus Rajewsky.

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Supplementary Figures 1–11, Tables 1–4 and Methods (PDF 1129 kb)

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Xiao, C., Srinivasan, L., Calado, D. et al. Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nat Immunol 9, 405–414 (2008). https://doi.org/10.1038/ni1575

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