Unknown

Dataset Information

0

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-?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.

SUBMITTER: Mishra A 

PROVIDER: S-EPMC3627362 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

Json Xml
altmetric image

Publications

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  ...[more]

Similar Datasets

Unknown Aberrant BUB1 Overexpression Promotes Mitotic Segregation Errors and Chromosomal Instability in Multiple Myeloma.
| S-EPMC7464435 | biostudies-literature
Unknown TP53 loss initiates chromosomal instability in fallopian tube epithelial cells.
| S-EPMC8649171 | biostudies-literature
Unknown STAT3 activation in large granular lymphocyte leukemia is associated with cytokine signaling and DNA hypermethylation.
| S-EPMC8632689 | biostudies-literature
Unknown Plk1 overexpression induces chromosomal instability and suppresses tumor development.
| S-EPMC6070485 | biostudies-literature
Unknown Preclinical and phase I clinical trial of blockade of IL-15 using Mikbeta1 monoclonal antibody in T cell large granular lymphocyte leukemia.
| S-EPMC1326174 | biostudies-literature
Transcriptomics TP53 loss initiates chromosomal instability in fallopian tube epithelial cells
2021-09-28 | GSE182487 | GEO
Unknown Increased serum soluble IL-15Rα levels in T-cell large granular lymphocyte leukemia.
| S-EPMC3251226 | biostudies-literature
Unknown Aberrant Wnt/beta-catenin signaling can induce chromosomal instability in colon cancer.
| S-EPMC1502302 | biostudies-literature
Unknown Interleukin-15 enhances proteasomal degradation of bid in normal lymphocytes: implications for large granular lymphocyte leukemias.
| S-EPMC2786937 | biostudies-literature
Unknown Aberrant Epigenetic Regulation in Head and Neck Cancer Due to Distinct EZH2 Overexpression and DNA Hypermethylation.
| S-EPMC6320890 | biostudies-other