Th17 cytokine differentiation and loss of plasticity after SOCS1 inactivation in a cutaneous T-cell lymphoma.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
Kadin, Marshall E
Drexler, Hans G
MacLeod, Roderick A F
MetadataShow full item record
AbstractWe 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.
CitationTh17 cytokine differentiation and loss of plasticity after SOCS1 inactivation in a cutaneous T-cell lymphoma. 2016: Oncotarget
AffiliationGerman Collection of Microorganisms and Cell Cultures, Department of Human and Animal Cell Cultures, Braunschweig, Germany.
The following license files are associated with this item:
- Jak3, STAT3, and STAT5 inhibit expression of miR-22, a novel tumor suppressor microRNA, in cutaneous T-Cell lymphoma.
- Authors: Sibbesen NA, Kopp KL, Litvinov IV, Jønson L, Willerslev-Olsen A, Fredholm S, Petersen DL, Nastasi C, Krejsgaard T, Lindahl LM, Gniadecki R, Mongan NP, Sasseville D, Wasik MA, Iversen L, Bonefeld CM, Geisler C, Woetmann A, Odum N
- Issue date: 2015 Aug 21
- t(8;9)(p22;p24)/PCM1-JAK2 activates SOCS2 and SOCS3 via STAT5.
- Authors: Ehrentraut S, Nagel S, Scherr ME, Schneider B, Quentmeier H, Geffers R, Kaufmann M, Meyer C, Prochorec-Sobieszek M, Ketterling RP, Knudson RA, Feldman AL, Kadin ME, Drexler HG, MacLeod RA
- Issue date: 2013
- Deregulation in STAT signaling is important for cutaneous T-cell lymphoma (CTCL) pathogenesis and cancer progression.
- Authors: Netchiporouk E, Litvinov IV, Moreau L, Gilbert M, Sasseville D, Duvic M
- Issue date: 2014
- Cutaneous T cell lymphoma expresses immunosuppressive CD80 (B7-1) cell surface protein in a STAT5-dependent manner.
- Authors: Zhang Q, Wang HY, Wei F, Liu X, Paterson JC, Roy D, Mihova D, Woetmann A, Ptasznik A, Odum N, Schuster SJ, Marafioti T, Riley JL, Wasik MA
- Issue date: 2014 Mar 15
- Differential effects of interleukin-2 and interleukin-15 versus interleukin-21 on CD4+ cutaneous T-cell lymphoma cells.
- Authors: Marzec M, Halasa K, Kasprzycka M, Wysocka M, Liu X, Tobias JW, Baldwin D, Zhang Q, Odum N, Rook AH, Wasik MA
- Issue date: 2008 Feb 15