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

Anjali Mishra, 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 ZhangPierluigi Porcu, Frederick K. Racke, Ramiro Garzon, Robert J. Lee, Guido Marcucci, Michael A. Caligiuri

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)645-655
Number of pages11
JournalCancer Cell
Volume22
Issue number5
DOIs
StatePublished - Nov 13 2012
Externally publishedYes

Bibliographical note

Funding 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.

Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.

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