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Cancer Discov. 2016 Sep;6(9):986-1005. doi: 10.1158/2159-8290.CD-15-1297. Epub 2016 Jul 15.

Mechanism, Consequences, and Therapeutic Targeting of Abnormal IL15 Signaling in Cutaneous T-cell Lymphoma.

Author information

1
Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio. Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio. Michael.Caligiuri@osumc.edu Anjali.Mishra@osumc.edu Pierluigi.Porcu@osumc.edu.
2
Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio. Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio.
3
Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio.
4
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
5
Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio. Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio.
6
Istituto Dermopatico dell'Immacolata-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
7
Centers for Biostatistics, The Ohio State University, Columbus, Ohio.
8
Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute, Norbert Gehr and Family Leukemia Center, City of Hope Medical Center, Duarte, California.
9
Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio. Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio. Michael.Caligiuri@osumc.edu Anjali.Mishra@osumc.edu Pierluigi.Porcu@osumc.edu.

Abstract

Cutaneous T-cell lymphoma (CTCL) is the most common type of primary cutaneous lymphoma. Here, we report that patients with CTCL show increased IL15 in a clinical stage-dependent manner. Mechanistically, we show that ZEB1 is a transcriptional repressor of IL15 in T cells and that hypermethylation of the ZEB1 binding region within the IL15 promoter, as seen in patients with CTCL, prevents ZEB1 binding and causes increased transcription of IL15 Using a transgenic mouse model of IL15, we provide evidence that overexpression of IL15 induces a spontaneous CTCL that mimics the human neoplasm. Excessive autocrine production of IL15 in T cells inhibits an HDAC1-mediated negative autoregulatory loop, resulting in the upregulation of HDAC1 and HDAC6 and transcriptional induction of the onco-miR-21. Interruption of IL15 downstream signaling with isotype-specific HDAC inhibitors halts (HDAC1) or significantly delays (HDAC6) the progression of CTCL in vivo and provides preclinical evidence supporting a hierarchical model of oncogenic signaling in CTCL.

SIGNIFICANCE:

To date, CTCL pathogenesis remains unknown, and there are no curative therapies. Our findings not only demonstrate a critical role for IL15-mediated inflammation in cutaneous T-cell lymphomagenesis, but also uncover a new oncogenic regulatory loop in CTCL involving IL15, HDAC1, HDAC6, and miR-21 that shows differential sensitivity to isotype-specific HDAC inhibitors. Cancer Discov; 6(9); 986-1005. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.

PMID:
27422033
PMCID:
PMC5388135
DOI:
10.1158/2159-8290.CD-15-1297
[Indexed for MEDLINE]
Free PMC Article

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