title: Aberrant overexpression of IL-15 initiates large granular lymphocyte leukemia through chromosomal instability and DNA hypermethylation.
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.
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Anjali
authors.initials: A
authors.lastname: Mishra
authors.forename: Shujun
authors.initials: S
authors.lastname: Liu
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Sams
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Curphey
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Santhanam
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Rush
authors.forename: Deanna
authors.initials: D
authors.lastname: Schaefer
authors.forename: Lauren G
authors.initials: LG
authors.lastname: Falkenberg
authors.forename: Laura
authors.initials: L
authors.lastname: Sullivan
authors.forename: Laura
authors.initials: L
authors.lastname: Jaroncyk
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Yang
authors.forename: Harold
authors.initials: H
authors.lastname: Fisk
authors.forename: Lai-Chu
authors.initials: LC
authors.lastname: Wu
authors.forename: Christopher
authors.initials: C
authors.lastname: Hickey
authors.forename: Jason C
authors.initials: JC
authors.lastname: Chandler
authors.forename: Yue-Zhong
authors.initials: YZ
authors.lastname: Wu
authors.forename: Nyla A
authors.initials: NA
authors.lastname: Heerema
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Chan
authors.forename: Danilo
authors.initials: D
authors.lastname: Perrotti
authors.forename: Jianying
authors.initials: J
authors.lastname: Zhang
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Porcu
authors.forename: Frederick K
authors.initials: FK
authors.lastname: Racke
authors.forename: Ramiro
authors.initials: R
authors.lastname: Garzon
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lee
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
mesh_terms: D000782:Aneuploidy; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018385:Centrosome / Q000502:physiology; D043171:Chromosomal Instability; D020090:Chromosome Segregation; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019409:Interleukin-15 / Q000235:genetics* / Q000378:metabolism; D054066:Leukemia, Large Granular Lymphocytic / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D019409:Interleukin-15; D035683:MicroRNAs; D000097584:DNA Methyltransferase 3B; C547014:MIRN29 microRNA, mouse