title: Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation.
abstract: Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, non-Hodgkin's lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation, which results in the formation of the nucleophosmin-anaplastic lymphoma tyrosine kinase (NPM-ALK) fusion protein (ALCL ALK(+)). However, little is known about the molecular features and tumour drivers in ALK-negative ALCL (ALCL ALK(-)), which is characterized by a worse prognosis. We found that ALCL ALK(-), in contrast to ALCL ALK(+), lymphomas display high miR-155 expression. Consistent with this, we observed an inverse correlation between miR-155 promoter methylation and miR-155 expression in ALCL. However, no direct effect of the ALK kinase on miR-155 levels was observed. Ago2 immunoprecipitation revealed miR-155 as the most abundant miRNA, and enrichment of target mRNAs C/EBPβ and SOCS1. To investigate its function, we over-expressed miR-155 in ALCL ALK(+) cell lines and demonstrated reduced levels of C/EBPβ and SOCS1. In murine engraftment models of ALCL ALK(-), we showed that anti-miR-155 mimics are able to reduce tumour growth. This goes hand-in-hand with increased levels of cleaved caspase-3 and high SOCS1 in these tumours, which leads to suppression of STAT3 signalling. Moreover, miR-155 induces IL-22 expression and suppresses the C/EBPβ target IL-8. These data suggest that miR-155 can act as a tumour driver in ALCL ALK(-) and blocking miR-155 could be therapeutically relevant. Original miRNA array data are to be found in the supplementary material (Table S1).
authors.affiliation: Department of Translational Oncology, National Centre for Tumour Diseases (NCT), German Cancer Research Centre (DKFZ), Heidelberg, Germany.|Department of Clinical Pathology, Medical University Vienna, Austria.|European Research Initiative on ALK Related Malignancies (www.erialcl.net).
authors.forename: Olaf
authors.initials: O
authors.lastname: Merkel
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, Third Medical Department, Oncologic Centre, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Frank
authors.initials: F
authors.lastname: Hamacher
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, Third Medical Department, Oncologic Centre, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Griessl
authors.affiliation: Department of Clinical Pathology, Medical University Vienna, Austria.
authors.forename: Lisa
authors.initials: L
authors.lastname: Grabner
authors.affiliation: Department of Clinical Pathology, Medical University Vienna, Austria.
authors.forename: Ana-Iris
authors.initials: AI
authors.lastname: Schiefer
authors.affiliation: Department of Clinical Pathology, Medical University Vienna, Austria.
authors.forename: Nicole
authors.initials: N
authors.lastname: Prutsch
authors.affiliation: Department of Epigenomics and Cancer Risk Factors, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: Constance
authors.initials: C
authors.lastname: Baer
authors.affiliation: Department of Clinical Pathology, Medical University Vienna, Austria.|European Research Initiative on ALK Related Malignancies (www.erialcl.net).
authors.forename: Gerda
authors.initials: G
authors.lastname: Egger
authors.affiliation: Department of Clinical Pathology, Medical University Vienna, Austria.|Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schlederer
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, Third Medical Department, Oncologic Centre, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Peter William
authors.initials: PW
authors.lastname: Krenn
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, Third Medical Department, Oncologic Centre, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Tanja Nicole
authors.initials: TN
authors.lastname: Hartmann
authors.affiliation: Department of Clinical Pathology, Medical University Vienna, Austria.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Simonitsch-Klupp
authors.affiliation: Department of Epigenomics and Cancer Risk Factors, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.affiliation: Division of Hematology and Hemostaseology, Comprehensive Cancer Centre Vienna, Medical University of Vienna, 1090, Vienna, Austria.
authors.forename: Philipp Bernhard
authors.initials: PB
authors.lastname: Staber
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna and Medical University of Vienna, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Moriggl
authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, UK.|European Research Initiative on ALK Related Malignancies (www.erialcl.net).
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: Turner
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, Third Medical Department, Oncologic Centre, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Greil
authors.affiliation: Department of Clinical Pathology, Medical University Vienna, Austria.|Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Unit of Pathology of Laboratory Animals, University of Veterinary Medicine Vienna, Austria.|European Research Initiative on ALK Related Malignancies (www.erialcl.net).
authors.forename: Lukas
authors.initials: L
authors.lastname: Kenner
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002889:Chromosomes, Human, Pair 2; D002895:Chromosomes, Human, Pair 5; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014178:Translocation, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; C108944:SOCS1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C505407:CASP3 protein, human; D053148:Caspase 3
keywords: ALCL; ALK kinase; IL-10; IL-21; IL-22; cytokines; miR-155
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