How inflammation causes cancer is unclear. Interleukin-15 (IL-15) is a pro-inflammatory cytokine elevated in human large granular lymphocyte (LGL) leukemia. Mice overexpressing IL-15 develop LGL leukemia. Here, we show that prolonged in vitro exposure of wild-type (WT) LGL to IL-15 results in Myc-mediated upregulation of aurora kinases, centrosome aberrancies, and aneuploidy. Simultaneously, IL-15 represses miR-29b via induction of Myc/NF-κBp65/Hdac-1, resulting in Dnmt3b overexpression and DNA hypermethylation. All this is validated in human LGL leukemia. Adoptive transfer of WT LGL cultured with IL-15 led to malignant transformation in vivo. Drug targeting that reverses miR-29b repression cures otherwise fatal LGL leukemia. We show how excessive IL-15 initiates cancer and demonstrate effective drug targeting for potential therapy of human LGL leukemia.
Bibliographical noteFunding Information:
This work is supported by National Cancer Institute Grants CA16058, CA95426, CA68458, CA09338 (to M.A.C.); CA140158 (to M.A.C. and G.M.); CA102031 (to G.M.); CA149623 (to S.L.); and NSF EEC-0914790 (to R.J.L.). The authors wish to thank Kathleen McConnell for technical assistance; we thank Mr. and Mrs. Thomas Lauber and Greif, Inc. for their support.