Temporal Dynamics of SMARCA4 Loss Define Its Role in Myogenic Differentiation of Alveolar Rhabdomyosarcoma
- 1Children's Cancer Therapy Development Institute
Abstract
SMARCA4 (BRG1) is a critical ATPase subunit of canonical BAF complexes and a known long term dependency in alveolar rhabdomyosarcoma (ARMS). To define the short term consequences of SMARCA4 loss, we used a doxycycline inducible shRNA system in Rh4 cells. Doxycycline treatment produced strong SMARCA4 knockdown, yet acute knockdown did not alter proliferation or induce myogenic differentiation. Ki 67 positivity remained unchanged, and Myosin Heavy Chain (MHC) expression was absent, indicating preservation of the undifferentiated, proliferative ARMS phenotype. These findings contrast with CRISPR mediated SMARCA4 knockout studies, which report cell cycle exit and robust differentiation, suggesting that ARMS cells tolerate partial or early phase SMARCA4 loss without destabilizing BAF complex function or PAX3 FOXO1 driven regulatory circuitry. Together with prior long term knockdown studies, our results support a model in which SMARCA4 dependency in ARMS is a sustained phenomenon requiring deep, prolonged suppression to trigger differentiation and loss of tumor viability.
Related
- Myogenic and neural transcriptional circuitry determines PAX3::FOXO1 driven initiation of rhabdomyosarcoma
- Cerebral Blood Flow–Derived Myogenic Dynamics Reveal Impaired Postischemic Cerebrovascular Recovery in Experimental Stroke
- Integrative phenotypic and transcriptomic validation of an alveolar-like macrophage model reveals early host–pathogen dynamics during Aspergillus fumigatus infection
- DEGS1-mTORC1-driven lipid metabolic reprogramming fuels rhabdomyosarcoma progression and unveils a therapeutic vulnerability
- Synergistic targeting of EP300/CBP and EYA co-activators collapses the rhabdomyosarcoma core regulatory circuit
BibTeX
@misc{keller2026temporal,
title = {{Temporal Dynamics of SMARCA4 Loss Define Its Role in Myogenic Differentiation of Alveolar Rhabdomyosarcoma}},
author = {C. Keller and N. B. Elangovan and C. C. Jennings and E. Lashyro and J. Wang and G. St. John},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.20.760536},
url = {https://www.biorxiv.org/content/10.64898/2026.10.20.760536v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Temporal Dynamics of SMARCA4 Loss Define Its Role in Myogenic Differentiation of Alveolar Rhabdomyosarcoma
AU - C. Keller
AU - N. B. Elangovan
AU - C. C. Jennings
AU - E. Lashyro
AU - J. Wang
AU - G. St. John
PY - 2026
DA - 2026/10/20
PB - bioRxiv
DO - 10.64898/2026.10.20.760536
UR - https://www.biorxiv.org/content/10.64898/2026.10.20.760536v1
AB - SMARCA4 (BRG1) is a critical ATPase subunit of canonical BAF complexes and a known long term dependency in alveolar rhabdomyosarcoma (ARMS). To define the short term consequences of SMARCA4 loss, we used a doxycycline inducible shRNA system in Rh4 cells. Doxycycline treatment produced strong SMARCA4 knockdown, yet acute knockdown did not alter proliferation or induce myogenic differentiation. Ki 67 positivity remained unchanged, and Myosin Heavy Chain (MHC) expression was absent, indicating preservation of the undifferentiated, proliferative ARMS phenotype. These findings contrast with CRISPR mediated SMARCA4 knockout studies, which report cell cycle exit and robust differentiation, suggesting that ARMS cells tolerate partial or early phase SMARCA4 loss without destabilizing BAF complex function or PAX3 FOXO1 driven regulatory circuitry. Together with prior long term knockdown studies, our results support a model in which SMARCA4 dependency in ARMS is a sustained phenomenon requiring deep, prolonged suppression to trigger differentiation and loss of tumor viability.
ER -