SMARCA4 biology in alveolar rhabdomyosarcoma

Bharathy, Narendra, Cleary, Megan M, Kim, Jin-Ah, Nagamori, Kiyo, Crawford, Kenneth A, Wang, Eric, Saha, Debarya, Settelmeyer, Teagan P, Purohit, Reshma, Skopelitis, Damianos, Chang, Kenneth, Doran, Jessica A, Kirschbaum, C Ward, Bharathy, Suriya, Crews, Davis W, Randolph, Matthew E, Karnezis, Anthony N, Hudson-Price, Lisa, Dhawan, Jyotsna, Michalek, Joel E, Ciulli, Alessio, Vakoc, Christopher R, Keller, Charles (January 2022) SMARCA4 biology in alveolar rhabdomyosarcoma. Oncogene. ISSN 0950-9232

DOI: 10.1038/s41388-022-02205-0


Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and phenocopies a muscle precursor that fails to undergo terminal differentiation. The alveolar subtype (ARMS) has the poorest prognosis and represents the greatest unmet medical need for RMS. Emerging evidence supports the role of epigenetic dysregulation in RMS. Here we show that SMARCA4/BRG1, an ATP-dependent chromatin remodeling enzyme of the SWI/SNF complex, is prominently expressed in primary tumors from ARMS patients and cell cultures. Our validation studies for a CRISPR screen of 400 epigenetic targets identified SMARCA4 as a unique factor for long-term (but not short-term) tumor cell survival in ARMS. A SMARCA4/SMARCA2 protein degrader (ACBI-1) demonstrated similar long-term tumor cell dependence in vitro and in vivo. These results credential SMARCA4 as a tumor cell dependency factor and a therapeutic target in ARMS.

Item Type: Paper
Subjects: Investigative techniques and equipment > CRISPR-Cas9
diseases & disorders > cancer > prognosis
diseases & disorders > cancer > cancer types > rhabdomyosarcoma
CSHL Authors:
Communities: CSHL labs > Chang lab
CSHL labs > Vakoc lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 29 January 2022
Date Deposited: 03 Feb 2022 16:39
Last Modified: 03 Feb 2022 16:39

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