Targeting of canonical WNT signaling ameliorates experimental sclerodermatous chronic graft-versus-host disease.
Blood
; 137(17): 2403-2416, 2021 04 29.
Article
en En
| MEDLINE
| ID: mdl-33529322
ABSTRACT
Chronic graft-versus-host disease (cGVHD) is a major life-threatening complication of allogeneic hematopoietic stem cell transplantation. The molecular mechanisms underlying cGVHD remain poorly understood, and targeted therapies for clinical use are not well established. Here, we examined the role of the canonical WNT pathway in sclerodermatous cGVHD (sclGVHD). WNT signaling was activated in human sclGVHD with increased nuclear accumulation of the transcription factor ß-catenin and a WNT-biased gene expression signature in lesional skin. Treatment with the highly selective tankryase inhibitor G007-LK, the CK1α agonist pyrvinium, or the LRP6 inhibitor salinomycin abrogated the activation of WNT signaling and protected against experimental cGVHD, without a significant impact on graft-versus-leukemia effect (GVL). Treatment with G007-LK, pyrvinium, or salinomycin almost completely prevented the development of clinical and histological features in the B10.D2 (H-2d) â BALB/c (H-2d) and LP/J (H-2b) â C57BL/6 (H-2b) models of sclGVHD. Inhibition of canonical WNT signaling reduced the release of extracellular matrix from fibroblasts and reduced leukocyte influx, suggesting that WNT signaling stimulates fibrotic tissue remodeling by direct effects on fibroblasts and by indirect inflammation-dependent effects in sclGVHD. Our findings may have direct translational potential, because pyrvinium is in clinical use, and tankyrase inhibitors are in clinical trials for other indications.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Piranos
/
Compuestos de Pirvinio
/
Esclerodermia Sistémica
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Sulfonas
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Triazoles
/
Trasplante de Células Madre Hematopoyéticas
/
Vía de Señalización Wnt
/
Enfermedad Injerto contra Huésped
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Límite:
Animals
/
Female
/
Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Blood
Año:
2021
Tipo del documento:
Article
País de afiliación:
Alemania