Developmental reprogramming underlies chemotherapy resistance in favorable-histology Wilms tumor

  • Cell Rep. 2026 Mar 24;45(3):117063. doi: 10.1016/j.celrep.2026.117063.
Andrew M Fleming  1 ,  Carolyn M Jablonowski  2 ,  Hongjian Jin  3 ,  Siwei Zhang  3 ,  Surbhi Sona  3 ,  Ha Won Lee  4 ,  Karissa M Dieseldorff Jones  5 ,  Changde Cheng  6 ,  Beisi Xu  3 ,  Christopher L Morton  2 ,  Mary A Woolard  2 ,  Prahalathan Pichavaram  2 ,  Daniel B Gehle  1 ,  Sivaraman Natarajan  6 ,  Kiran Kodali  7 ,  Vishwajeeth Pagala  7 ,  Anthony A High  7 ,  Yogesh Kumar  3 ,  Steven Burden  8 ,  Virginia Valentine  8 ,  Deidre Daria  9 ,  Jake Harbour  9 ,  Daniel Vocelle  9 ,  Ti-Cheng Chang  3 ,  John Easton  6 ,  Scott R Olsen  10 ,  Geoffrey Neale  10 ,  Emilia M Pinto  5 ,  Jerold E Rehg  5 ,  Laura Janke  5 ,  Teresa Santiago  5 ,  Rani E George  11 ,  Xiaotu Ma  6 ,  Gerard P Zambetti  5 ,  Andrew M Davidoff  1 ,  Taosheng Chen  4 ,  Gang Wu  3 ,  Xiang Chen  6 ,  Jun Yang  1 ,  Andrew J Murphy  12
Affiliations
  • 1. 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.
  • 2. St. Jude Children's Research Hospital, Department of Surgery, Memphis, TN, USA.
  • 3. St. Jude Children's Research Hospital, Center for Applied Bioinformatics, Memphis, TN, USA.
  • 4. St. Jude Children's Research Hospital, Department of Chemical Biology and Therapeutics, Memphis, TN, USA.
  • 5. St. Jude Children's Research Hospital, Department of Pathology, Memphis, TN, USA.
  • 6. St. Jude Children's Research Hospital, Department of Computational Biology, Memphis, TN, USA.
  • 7. St. Jude Children's Research Hospital, Center for Proteomics and Metabolomics, Memphis, TN, USA.
  • 8. St. Jude Children's Research Hospital, Cytogenetics Shared Resource, Memphis, TN, USA.
  • 9. St. Jude Children's Research Hospital, Flow Cytometry and Cell Sorting Shared Resource, Memphis, TN, USA.
  • 10. St. Jude Children's Research Hospital, Hartwell Center for Biotechnology, Memphis, TN, USA.
  • 11. Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
  • 12. 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: [email protected].
PMID: 41850280 DOI: 10.1016/j.celrep.2026.117063
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.

Keywords
ABCB1; CP: cancer; LIN28B; MYCN; N-MYC; Wilms tumor; chemotherapy resistance; kidney development.
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