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Oncotarget. 2016 Jun 7;7(23):34201-16. doi: 10.18632/oncotarget.9077.

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

Author information

1
Leibniz Institute - DSMZ, German Collection of Microorganisms and Cell Cultures, Department of Human and Animal Cell Cultures, Braunschweig, Germany.
2
University of Rostock, Institute of Pathology and Molecular Pathology, Rostock, Germany.
3
HZI - Helmholtz Center for Infection Research, Genome Analytics Research Group, Braunschweig, Germany.
4
University Medical Center Goettingen, Department of Haematology and Medical Oncology, Goettingen, Germany.
5
Department of Dermatology and Skin Surgery, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI, USA.

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.

KEYWORDS:

CTCL; IL-17F; IL-2; JAK3; SOCS1

PMID:
27144517
PMCID:
PMC5085149
DOI:
10.18632/oncotarget.9077
[Indexed for MEDLINE]
Free PMC Article

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