Author/Authors :
Mishra، نويسنده , , Anjali and Liu، نويسنده , , Shujun and Sams، نويسنده , , Gregory H. and Curphey، نويسنده , , Douglas P. and Santhanam، نويسنده , , Ramasamy and Rush، نويسنده , , Laura J. and Schaefer، نويسنده , , Deanna and Falkenberg، نويسنده , , Lauren G. and Sullivan، نويسنده , , Laura and Jaroncyk، نويسنده , , Laura L.M. Yang، نويسنده , , Xiaojuan and Fisk، نويسنده , , Harold and Wu، نويسنده , , Lai-Chu and Hickey، نويسنده , , Christopher and Chandler، نويسنده , , Jason C. and Wu، نويسنده , , Yue-Zhong and Heerema، نويسنده , , Nyla A. and Chan، نويسنده , , Kenneth K. and Perrotti، نويسنده , , Danilo and Zhang، نويسنده , , Jianying and Porcu، نويسنده , , Pierluigi and Racke، نويسنده , , Frederick K. and Garzon، نويسنده , , Ramiro and Lee، نويسنده , , Robert J. and Marcucci، نويسنده , , Guido and Caligiuri، نويسنده , , Michael A.، نويسنده ,
Abstract :
Summary
flammation 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.
