Zhang, Yun and Shen, Lichong and Dreissigacker, Katja and Zhu, Honglin and Thuong Trinh-Minh, and Meng, Xianyi and Cuong Tran-Manh, and Dees, Clara and Matei, Alexandru-Emil and Chen, Chih-Wei and Ditschkowski, Markus and Krauss, Stefan and Winkler, Julia and Wolff, Daniel and Ziemer, Mirjana and Beilhack, Andreas and Karrer, Sigrid and Herr, Wolfgang and Mackensen, Andreas and Schett, Georg and Spriewald, Bernd M. and Distler, Joerg H. W. (2021) Targeting of canonical WNT signaling ameliorates experimental sclerodermatous chronic graft-versus-host disease. BLOOD, 137 (17). pp. 2403-2416. ISSN 0006-4971, 1528-0020
Full text not available from this repository. (Request a copy)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 beta-catenin and a WNT-biased gene expression signature in lesional skin. Treatment with the highly selective tankryase inhibitor G007-LK, the CK1 alpha 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-2(d)) -> BALB/c (H-2(d)) and LP/J (H-2(b)) -> C57BL/6 (H-2(b)) 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SYSTEMIC-SCLEROSIS; INHIBITION; FIBROSIS; ACTIVATION; PATHWAY; MODEL; CELLS; FATE; MICE; TCF1; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Dermatologie und Venerologie Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 13 Sep 2022 15:04 |
| Last Modified: | 13 Sep 2022 15:04 |
| URI: | https://pred.uni-regensburg.de/id/eprint/47374 |
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