Targeting of canonical WNT signaling ameliorates experimental sclerodermatous chronic graft-versus-host disease

Author:

Zhang Yun12ORCID,Shen Lichong12,Dreißigacker Katja12,Zhu Honglin123ORCID,Trinh-Minh Thuong12,Meng Xianyi12,Tran-Manh Cuong12,Dees Clara12ORCID,Matei Alexandru-Emil12ORCID,Chen Chih-Wei12,Ditschkowski Markus4ORCID,Krauss Stefan5,Winkler Julia6,Wolff Daniel7,Ziemer Mirjana8,Beilhack Andreas9,Karrer Sigrid10ORCID,Herr Wolfgang7,Mackensen Andreas6ORCID,Schett Georg12,Spriewald Bernd M.6,Distler Jörg H. W.12ORCID

Affiliation:

1. Department of Internal Medicine III–Rheumatology and Immunology, University of Erlangen-Nuremberg, Erlangen, Germany;

2. Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg–University Hospital Erlangen, Erlangen, Germany;

3. Xiangya Hospital, Central South University, Changsha, China;

4. Department of Bone Marrow Transplantation, University Hospital Essen, Essen, Germany;

5. Faculty of Medicine, University of Oslo, Oslo, Norway;

6. Department of Internal Medicine V–Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany;

7. Department of Internal Medicine III, Hematology, and Internal Oncology, University Hospital Regensburg, Regensburg, Germany;

8. Department of Dermatology, Venerology, and Allergology, University Medical Center Leipzig, Leipzig, Germany;

9. Department of Medicine II, University Hospital Würzburg, Wurzburg, Germany; and

10. Department of Dermatology, University Hospital Regensburg, Regensburg, Germany

Abstract

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 β-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) → BALB/c (H-2d) and LP/J (H-2b) → 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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