title: Mechanism, Consequences, and Therapeutic Targeting of Abnormal IL15 Signaling in Cutaneous T-cell Lymphoma.
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.
  
  
  
  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.
authors.affiliation: 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.
authors.forename: Anjali
authors.initials: A
authors.lastname: Mishra
authors.affiliation: 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.
authors.forename: Krista
authors.initials: K
authors.lastname: La Perle
authors.affiliation: Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio.
authors.forename: Sonya
authors.initials: S
authors.lastname: Kwiatkowski
authors.affiliation: Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Sullivan
authors.affiliation: Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio.
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Sams
authors.affiliation: Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio.
authors.forename: Jessica
authors.initials: J
authors.lastname: Johns
authors.affiliation: Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio.
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Curphey
authors.affiliation: Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio.
authors.forename: Jing
authors.initials: J
authors.lastname: Wen
authors.affiliation: Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio.
authors.forename: Kathleen
authors.initials: K
authors.lastname: McConnell
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jun
authors.initials: J
authors.lastname: Qi
authors.affiliation: 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.
authors.forename: Henry
authors.initials: H
authors.lastname: Wong
authors.affiliation: Istituto Dermopatico dell'Immacolata-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
authors.forename: Giandomenico
authors.initials: G
authors.lastname: Russo
authors.affiliation: Centers for Biostatistics, The Ohio State University, Columbus, Ohio.
authors.forename: Jianying
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute, Norbert Gehr and Family Leukemia Center, City of Hope Medical Center, Duarte, California.
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: 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.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Porcu
authors.affiliation: 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.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D056284:Histone Deacetylase 1 / Q000096:biosynthesis / Q000235:genetics*; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology / Q000628:therapy; D019409:Interleukin-15 / Q000235:genetics*; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000235:genetics; D015398:Signal Transduction; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics
chemical_list: D056572:Histone Deacetylase Inhibitors; C569274:IL15 protein, human; D019409:Interleukin-15; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; C110550:HDAC1 protein, human; C433811:HDAC6 protein, human; D056284:Histone Deacetylase 1; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases