Research Papers:

Th17 cytokine differentiation and loss of plasticity after SOCS1 inactivation in a cutaneous T-cell lymphoma

Stefan Ehrentraut, Björn Schneider, Stefan Nagel, Claudia Pommerenke, Hilmar Quentmeier, Robert Geffers, Maren Feist, Maren Kaufmann, Corinna Meyer, Marshall E. Kadin, Hans G. Drexler and Roderick A. F. MacLeod _

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Oncotarget. 2016; 7:34201-34216. https://doi.org/10.18632/oncotarget.9077

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Stefan Ehrentraut1, Björn Schneider2, Stefan Nagel1, Claudia Pommerenke1, Hilmar Quentmeier1, Robert Geffers3, Maren Feist4, Maren Kaufmann1, Corinna Meyer1, Marshall E. Kadin5, Hans G. Drexler1, Roderick A. F. MacLeod1

1Leibniz Institute - DSMZ, German Collection of Microorganisms and Cell Cultures, Department of Human and Animal Cell Cultures, Braunschweig, Germany

2University of Rostock, Institute of Pathology and Molecular Pathology, Rostock, Germany

3HZI - Helmholtz Center for Infection Research, Genome Analytics Research Group, Braunschweig, Germany

4University Medical Center Goettingen, Department of Haematology and Medical Oncology, Goettingen, Germany

5Department of Dermatology and Skin Surgery, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI, USA

Correspondence to:

Roderick A.F. MacLeod, email: [email protected]

Keywords: CTCL, IL-2, IL-17F, JAK3, SOCS1

Received: February 03, 2016     Accepted: April 10, 2016     Published: April 28, 2016


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.

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