title: Th17 cytokine differentiation and loss of plasticity after SOCS1 inactivation in a cutaneous T-cell lymphoma.
abstract: We propose that deregulated T-helper-cell (Th) signaling underlies evolving Th17 cytokine expression seen during progression of cutaneous T-cell lymphoma (CTCL). Accordingly, we developed a lymphoma progression model comprising cell lines established at indolent (MAC-1) and aggressive (MAC-2A) CTCL stages. We discovered activating JAK3 (V722I) mutations present at indolent disease, reinforced in aggressive disease by novel compound heterozygous SOCS1 (G78R/D105N) JAK-binding domain inactivating mutations. Though isogenic, indolent and aggressive-stage cell lines had diverged phenotypically, the latter expressing multiple Th17 related cytokines, the former a narrower profile. Importantly, indolent stage cells remained poised for Th17 cytokine expression, readily inducible by treatment with IL-2 - a cytokine which mitigates Th17 differentiation in mice. In indolent stage cells JAK3 expression was boosted by IL-2 treatment. Th17 conversion of MAC-1 cells by IL-2 was blocked by pharmacological inhibition of JAK3 or STAT5, implicating IL2RG - JAK3 - STAT5 signaling in plasticity responses. Like IL-2 treatment, SOCS1 knockdown drove indolent stage cells to mimic key aggressive stage properties, notably IL17F upregulation. Co-immunoprecipitation experiments showed that SOCS1 mutations abolished JAK3 binding, revealing a key role for SOCS1 in regulating JAK3/STAT5 signaling. Collectively, our results show how JAK/STAT pathway mutations contribute to disease progression in CTCL cells by potentiating inflammatory cytokine signaling, widening the potential therapeutic target range for this intractable entity. MAC-1/2A cells also provide a candidate human Th17 laboratory model for identifying potentally actionable CTCL markers or targets and testing their druggability in vitro.
authors.affiliation: Leibniz Institute - DSMZ, German Collection of Microorganisms and Cell Cultures, Department of Human and Animal Cell Cultures, Braunschweig, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ehrentraut
authors.affiliation: University of Rostock, Institute of Pathology and Molecular Pathology, Rostock, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Schneider
authors.affiliation: Leibniz Institute - DSMZ, German Collection of Microorganisms and Cell Cultures, Department of Human and Animal Cell Cultures, Braunschweig, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Nagel
authors.affiliation: Leibniz Institute - DSMZ, German Collection of Microorganisms and Cell Cultures, Department of Human and Animal Cell Cultures, Braunschweig, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pommerenke
authors.affiliation: Leibniz Institute - DSMZ, German Collection of Microorganisms and Cell Cultures, Department of Human and Animal Cell Cultures, Braunschweig, Germany.
authors.forename: Hilmar
authors.initials: H
authors.lastname: Quentmeier
authors.affiliation: HZI - Helmholtz Center for Infection Research, Genome Analytics Research Group, Braunschweig, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.affiliation: University Medical Center Goettingen, Department of Haematology and Medical Oncology, Goettingen, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Feist
authors.affiliation: Leibniz Institute - DSMZ, German Collection of Microorganisms and Cell Cultures, Department of Human and Animal Cell Cultures, Braunschweig, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Kaufmann
authors.affiliation: Leibniz Institute - DSMZ, German Collection of Microorganisms and Cell Cultures, Department of Human and Animal Cell Cultures, Braunschweig, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Meyer
authors.affiliation: Department of Dermatology and Skin Surgery, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI, USA.
authors.forename: Marshall E
authors.initials: ME
authors.lastname: Kadin
authors.affiliation: Leibniz Institute - DSMZ, German Collection of Microorganisms and Cell Cultures, Department of Human and Animal Cell Cultures, Braunschweig, Germany.
authors.forename: Hans G
authors.initials: HG
authors.lastname: Drexler
authors.affiliation: Leibniz Institute - DSMZ, German Collection of Microorganisms and Cell Cultures, Department of Human and Animal Cell Cultures, Braunschweig, Germany.
authors.forename: Roderick A F
authors.initials: RA
authors.lastname: MacLeod
mesh_terms: D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology; D006801:Humans; D053616:Janus Kinase 3 / Q000235:genetics / Q000378:metabolism; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D009154:Mutation; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000235:genetics / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D016207:Cytokines; C108944:SOCS1 protein, human; D050799:STAT5 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; C507933:JAK3 protein, human; D053616:Janus Kinase 3
keywords: CTCL; IL-17F; IL-2; JAK3; SOCS1