| Literature DB >> 23153537 |
Anjali Mishra1, Shujun Liu, Gregory H Sams, Douglas P Curphey, Ramasamy Santhanam, Laura J Rush, Deanna Schaefer, Lauren G Falkenberg, Laura Sullivan, Laura Jaroncyk, Xiaojuan Yang, Harold Fisk, Lai-Chu Wu, Christopher Hickey, Jason C Chandler, Yue-Zhong Wu, Nyla A Heerema, Kenneth K Chan, Danilo Perrotti, Jianying Zhang, Pierluigi Porcu, Frederick K Racke, Ramiro Garzon, Robert J Lee, Guido Marcucci, Michael A Caligiuri.
Abstract
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.Entities:
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Year: 2012 PMID： 23153537 PMCID： PMC3627362 DOI： 10.1016/j.ccr.2012.09.009
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743