Aberrant Overexpression of IL-15 Initiates Large Granular Lymphocyte Leukemia through Chromosomal Instability and DNA Hypermethylation

作者：Mishra Anjali; Liu Shujun; Sams Gregory H; Curphey Douglas P; Santhanam Ramasamy; Rush Laura J; Schaefer Deanna; Falkenberg Lauren G; Sullivan Laura; Jaroncyk Laura; Yang Xiaojuan; Fisk Harold; Wu Lai Chu; Hickey Christopher; Chandler Jason C; Wu Yue Zhong; Heerema Nyla A; Chan Kenneth K; Perrotti Danilo; Zhang Jianying; Porcu Pierluigi; Racke Frederick K; Garzon Ramiro; Lee Robert J; Marcucci Guido^*; Caligiuri Michael A

来源：Cancer Cell, 2012, 22(5): 645-655.

DOI：10.1016/j.ccr.2012.09.009

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-kappa Bp65/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.

• 出版日期2012-11-13