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


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.


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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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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).

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