title: STAT3/5-Dependent IL9 Overexpression Contributes to Neoplastic Cell Survival in Mycosis Fungoides.
abstract: Sustained inflammation is a key feature of mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL). Resident IL9-producing T cells have been found in skin infections and certain inflammatory skin diseases, but their role in MF is currently unknown.
  
  
  
  We analyzed lesional skin from patients with MF for the expression of IL9 and its regulators. To determine which cells were producing IL9, high-throughput sequencing was used to identify malignant clones and Vb-specific antibodies were employed to visualize malignant cells in histologic preparations. To explore the mechanism of IL9 secretion, we knocked down STAT3/5 and IRF4 by siRNA transfection in CTCL cell lines receiving psoralen+UVA (PUVA) ± anti-IL9 antibody. To further examine the role of IL9 in tumor development, the EL-4 T-cell lymphoma model was used in C57BL/6 mice.
  
  
  
  Malignant and reactive T cells produce IL9 in lesional skin. Expression of the Th9 transcription factor IRF4 in malignant cells was heterogeneous, whereas reactive T cells expressed it uniformly. PUVA or UVB phototherapy diminished the frequencies of IL9- and IL9r-positive cells, as well as STAT3/5a and IRF4 expression in lesional skin. IL9 production was regulated by STAT3/5 and silencing of STAT5 or blockade of IL9 with neutralizing antibodies potentiated cell death after PUVA treatment in vitro IL9-depleted mice exhibited a reduction of tumor growth, higher frequencies of regulatory T cells, and activated CD4 and CD8 T lymphocytes.
  
  
  
  Our results suggest that IL9 and its regulators are promising new targets for therapy development in mycosis fungoides. Clin Cancer Res; 22(13); 3328-39. ©2016 AACR.
authors: Research Unit for Photodermatology, Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria.
authors: Pablo A
authors: PA
authors: Vieyra-Garcia
authors: Department of Dermatology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
authors: Tianling
authors: T
authors: Wei
authors: Department of Dermatology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
authors: David Gram
authors: DG
authors: Naym
authors: Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors: Simon
authors: S
authors: Fredholm
authors: Research Unit for Photodermatology, Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria.
authors: Regina
authors: R
authors: Fink-Puches
authors: Research Unit for Photodermatology, Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria.
authors: Lorenzo
authors: L
authors: Cerroni
authors: Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors: Niels
authors: N
authors: Odum
authors: Department of Dermatology, Brigham and Women's Hospital, Harvard University, Boston, Massachusetts.
authors: John T
authors: JT
authors: O'Malley
authors: Department of Dermatology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen, Denmark. Division of Dermatology, Department of Medicine, University of Alberta, Edmonton, Canada.
authors: Robert
authors: R
authors: Gniadecki
authors: Research Unit for Photodermatology, Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria. peter.wolf@medunigraz.at.
authors: Peter
authors: P
authors: Wolf
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D016906:Interleukin-9 / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009182:Mycosis Fungoides / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D016906:Interleukin-9; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D025521:Tumor Suppressor Proteins; D000099218:Interferon Regulatory Factor-4; C508607:IL9 protein, human; C494086:STAT3 protein, human; C494092:STAT5A protein, human