Developmental reprogramming underlies chemotherapy resistance in favorable-histology Wilms tumor.

Abstract

Children with favorable-histology Wilms tumor (FHWT) who relapse or whose tumors show blastemal predominance post-chemotherapy often face poor outcomes. The purpose of this study is to identify mechanisms of chemotherapy resistance in FHWT. We induce a patient-derived xenograft model (KT-47) to develop blastemal predominance after chemotherapy and to become resistant to vincristine, actinomycin-D, and doxorubicin (VAD). Multi-omics analyses reveal chromatin and transcriptional changes, including increased H3K4me3 and decreased H3K27me3 at stem cell and nephrogenesis gene loci. LIN28B is the most upregulated resistance-associated gene, linked to MYCN copy gain/upregulation and chromatin remodeling. ABCB1 expression correlates with interchromosomal enhancer interactions and functions as the mediator of chemotherapy resistance in vitro. These findings are validated in additional Wilms tumor models. Overall, resistance is associated with de-differentiation to a stem-like state and is driven by ABCB1 upregulation, suggesting that therapeutic strategies targeting chromatin regulation and drug efflux may be relevant in therapy-resistant Wilms tumor.
Copyright © 2026 The Author(s). Published by Elsevier Inc. All rights reserved.

Authors

Andrew M Fleming, Carolyn M Jablonowski, Hongjian Jin, Siwei Zhang, Surbhi Sona, Ha Won Lee, Karissa M Dieseldorff Jones, Changde Cheng, Beisi Xu, Christopher L Morton, Mary A Woolard, Prahalathan Pichavaram, Daniel B Gehle, Sivaraman Natarajan, Kiran Kodali, Vishwajeeth Pagala, Anthony A High, Yogesh Kumar, Steven Burden, Virginia Valentine, Deidre Daria, Jake Harbour, Daniel Vocelle, Ti-Cheng Chang, John Easton, Scott R Olsen, Geoffrey Neale, Emília M Pinto, Jerold E Rehg, Laura Janke, Teresa Santiago, Rani E George, Xiaotu Ma, Gerard P Zambetti, Andrew M Davidoff, Taosheng Chen, Gang Wu, Xiang Chen, Jun Yang, Andrew J Murphy

The University of Tennessee Health Science Center, Department of Surgery, Memphis, TN, USA; St. Jude Children's Research Hospital, Department of Surgery, Memphis, TN, USA. Electronic address: andrew.murphy@stjude.org.