FANCM is required for the PAX3::FOXO1-driven oncogenic program in rhabdomyosarcoma
5 affiliations
- 1Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
- 2INSERM UMR 944, IRSL, St Louis Hospital, University of Paris-Cité, Paris, France
- 3Broad Institute of MIT and Harvard, Cambridge, MA, USA
- 4Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
- 5Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street S.W., Rochester, MN 55905, USA
Abstract
SUMMARY: Many cancers are driven by mutationally altered transcription factors (TFs) that rewire cells to an oncogenic state. Cells must activate specific mechanisms to tolerate the burden of oncogenic TF activity. To define such mechanisms, we focused on a canonical oncogenic fusion protein-driven cancer, alveolar rhabdomyosarcoma (ARMS), where the PAX3::FOXO1 fusion protein hyperactivates and mislocalizes PAX3 and FOXO1 TF functions. Employing sequential functional genomic CRISPR-Cas9 screens, we identified FANCM, a DNA translocase in the Fanconi anemia pathway, as a selective dependency in PAX3::FOXO1+ ARMS. FANCM loss reduces fusion protein levels, induces myogenic differentiation, and disrupts the PAX3::FOXO1 transcriptional program, thereby halting oncogenic proliferation. Mechanistically, FANCM depletion exacerbates replication stress (RS) and DNA damage signaling, with chromatin-associated RS enriched at PAX3::FOXO1 target gene loci, resulting in selective downregulation of the oncogenic program. CRISPR exon-tiling screens prioritized FANCM’s helicase and DNA-binding domains as essential for this dependency, linking FANCM-mediated replication fork binding to sustained oncogenesis.
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BibTeX
@article{delaney2026fancm,
title = {{FANCM is required for the PAX3::FOXO1-driven oncogenic program in rhabdomyosarcoma}},
author = {Christopher D. Delaney and Min Lu and Seth P. Zimmerman and Yingying Meng and Camille Vaganay and Christian G. Cerda-Smith and Annie Liu and Jacob P. Hoj and Shane T. Killarney and Kerry Dillon and Amy E. Stewart and Kevin Huang and Julia D. Caci and Olivia White and Alexandre Puissant and David E. Root and Jack F. Shern and Christine E. Eyler and Chun-Wei David Chen and Christopher M. Counter and Corinne M. Linardic and Lee Zou and Kris C. Wood},
journal = {Cell reports},
year = {2026},
month = sep,
doi = {10.1016/j.celrep.2026.117960},
url = {https://europepmc.org/article/PMC/PMC13728430},
note = {CC BY},
}
RIS
TY - JOUR
TI - FANCM is required for the PAX3::FOXO1-driven oncogenic program in rhabdomyosarcoma
AU - Christopher D. Delaney
AU - Min Lu
AU - Seth P. Zimmerman
AU - Yingying Meng
AU - Camille Vaganay
AU - Christian G. Cerda-Smith
AU - Annie Liu
AU - Jacob P. Hoj
AU - Shane T. Killarney
AU - Kerry Dillon
AU - Amy E. Stewart
AU - Kevin Huang
AU - Julia D. Caci
AU - Olivia White
AU - Alexandre Puissant
AU - David E. Root
AU - Jack F. Shern
AU - Christine E. Eyler
AU - Chun-Wei David Chen
AU - Christopher M. Counter
AU - Corinne M. Linardic
AU - Lee Zou
AU - Kris C. Wood
PY - 2026
DA - 2026/09/08
JO - Cell reports
DO - 10.1016/j.celrep.2026.117960
UR - https://europepmc.org/article/PMC/PMC13728430
AB - SUMMARY: Many cancers are driven by mutationally altered transcription factors (TFs) that rewire cells to an oncogenic state. Cells must activate specific mechanisms to tolerate the burden of oncogenic TF activity. To define such mechanisms, we focused on a canonical oncogenic fusion protein-driven cancer, alveolar rhabdomyosarcoma (ARMS), where the PAX3::FOXO1 fusion protein hyperactivates and mislocalizes PAX3 and FOXO1 TF functions. Employing sequential functional genomic CRISPR-Cas9 screens, we identified FANCM, a DNA translocase in the Fanconi anemia pathway, as a selective dependency in PAX3::FOXO1+ ARMS. FANCM loss reduces fusion protein levels, induces myogenic differentiation, and disrupts the PAX3::FOXO1 transcriptional program, thereby halting oncogenic proliferation. Mechanistically, FANCM depletion exacerbates replication stress (RS) and DNA damage signaling, with chromatin-associated RS enriched at PAX3::FOXO1 target gene loci, resulting in selective downregulation of the oncogenic program. CRISPR exon-tiling screens prioritized FANCM’s helicase and DNA-binding domains as essential for this dependency, linking FANCM-mediated replication fork binding to sustained oncogenesis.
SN - 2211-1247
ER -