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

Zhang Y, Shen L, Dreißigacker K, Zhu H, Trinh MT, Meng X, TRAN MANH C, Dees C, Matei AE, Chen CW, Ditschkowski M, Krauss S, Winkler J, Wolff D, Ziemer M, Beilhack A, Karrer S, Herr W, Mackensen A, Schett G, Spriewald BM, Distler J (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Blood American Society of Hematology

Book Volume: 137

Pages Range: 2403-2416

Journal Issue: 17

DOI: 10.1182/blood.2020008720

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.

Authors with CRIS profile

Yun Zhang Department of Medicine 3 – Rheumatology and Immunology Lichong Shen Professur für Molekulare Mechanismen der Organfibrose Minh Thuong Trinh Department of Medicine 3 – Rheumatology and Immunology Xianyi Meng Juniorprofessur für Osteoimmunologie CUONG TRAN MANH Department of Medicine 3 – Rheumatology and Immunology Clara Dees Department of Medicine 3 – Rheumatology and Immunology Alexandru-Emil Matei Department of Medicine 3 – Rheumatology and Immunology Julia Winkler Department of Medicine 5 – Haematology and Oncology Andreas Mackensen Lehrstuhl für Innere Medizin V Georg Schett Lehrstuhl für Innere Medizin III Jörg Distler Professur für Molekulare Mechanismen der Organfibrose

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Related research project(s)

A079: The nuclear receptor TR4 regulates TGFbeta-induced fibroblast activation and tissue fibrosis Jan. 1, 2021 - June 30, 2023

Involved external institutions

Universitätsklinikum Regensburg DE Germany (DE) Universitätsklinikum Leipzig DE Germany (DE) Universitätsklinikum Würzburg DE Germany (DE) University of Oslo NO Norway (NO) Universitätsklinikum Essen DE Germany (DE)

How to cite

APA:

Zhang, Y., Shen, L., Dreißigacker, K., Zhu, H., Trinh, M.T., Meng, X.,... Distler, J. (2021). Targeting of canonical WNT signaling ameliorates experimental sclerodermatous chronic graft-versus-host disease. Blood, 137(17), 2403-2416. https://doi.org/10.1182/blood.2020008720

MLA:

Zhang, Yun, et al. "Targeting of canonical WNT signaling ameliorates experimental sclerodermatous chronic graft-versus-host disease." Blood 137.17 (2021): 2403-2416.

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