SMARCA4 biology in alveolar rhabdomyosarcoma

Narendra Bharathy; Megan M. Cleary; Jin Ah Kim; Kiyo Nagamori; Kenneth A. Crawford; Eric Wang; Debarya Saha; Teagan P. Settelmeyer; Reshma Purohit; Damianos Skopelitis; Kenneth Chang; Jessica A. Doran; C. Ward Kirschbaum; Suriya Bharathy; Davis W. Crews; Matthew E. Randolph; Anthony N. Karnezis; Lisa Hudson-Price; Jyotsna Dhawan; Joel E. Michalek; Alessio Ciulli; Christopher R. Vakoc; Charles Keller

doi:10.1038/s41388-022-02205-0

SMARCA4 biology in alveolar rhabdomyosarcoma

Narendra Bharathy, Megan M. Cleary, Jin Ah Kim, Kiyo Nagamori, Kenneth A. Crawford, Eric Wang, Debarya Saha, Teagan P. Settelmeyer, Reshma Purohit, Damianos Skopelitis, Kenneth Chang, Jessica A. Doran, C. Ward Kirschbaum, Suriya Bharathy, Davis W. Crews, Matthew E. Randolph, Anthony N. Karnezis, Lisa Hudson-Price, Jyotsna Dhawan, Joel E. MichalekAlessio Ciulli, Christopher R. Vakoc, Charles Keller

Department of Population Health Sciences

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	1647-1656
Number of pages	10
Journal	Oncogene
Volume	41
Issue number	11
DOIs	https://doi.org/10.1038/s41388-022-02205-0
State	Published - Mar 10 2022

ASJC Scopus subject areas

Genetics
Molecular Biology
Cancer Research

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Bharathy, N., Cleary, M. M., Kim, J. A., Nagamori, K., Crawford, K. A., Wang, E., Saha, D., Settelmeyer, T. P., Purohit, R., Skopelitis, D., Chang, K., Doran, J. A., Kirschbaum, C. W., Bharathy, S., Crews, D. W., Randolph, M. E., Karnezis, A. N., Hudson-Price, L., Dhawan, J., ... Keller, C. (2022). SMARCA4 biology in alveolar rhabdomyosarcoma. Oncogene, 41(11), 1647-1656. https://doi.org/10.1038/s41388-022-02205-0

Bharathy, N, Cleary, MM, Kim, JA, Nagamori, K, Crawford, KA, Wang, E, Saha, D, Settelmeyer, TP, Purohit, R, Skopelitis, D, Chang, K, Doran, JA, Kirschbaum, CW, Bharathy, S, Crews, DW, Randolph, ME, Karnezis, AN, Hudson-Price, L, Dhawan, J, Michalek, JE, Ciulli, A, Vakoc, CR & Keller, C 2022, 'SMARCA4 biology in alveolar rhabdomyosarcoma', Oncogene, vol. 41, no. 11, pp. 1647-1656. https://doi.org/10.1038/s41388-022-02205-0

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abstract = "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.",

author = "Narendra Bharathy and Cleary, {Megan M.} and Kim, {Jin Ah} and Kiyo Nagamori and Crawford, {Kenneth A.} and Eric Wang and Debarya Saha and Settelmeyer, {Teagan P.} and Reshma Purohit and Damianos Skopelitis and Kenneth Chang and Doran, {Jessica A.} and Kirschbaum, {C. Ward} and Suriya Bharathy and Crews, {Davis W.} and Randolph, {Matthew E.} and Karnezis, {Anthony N.} and Lisa Hudson-Price and Jyotsna Dhawan and Michalek, {Joel E.} and Alessio Ciulli and Vakoc, {Christopher R.} and Charles Keller",

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AU - Cleary, Megan M.

AU - Kim, Jin Ah

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AU - Wang, Eric

AU - Saha, Debarya

AU - Settelmeyer, Teagan P.

AU - Purohit, Reshma

AU - Skopelitis, Damianos

AU - Chang, Kenneth

AU - Doran, Jessica A.

AU - Kirschbaum, C. Ward

AU - Bharathy, Suriya

AU - Crews, Davis W.

AU - Randolph, Matthew E.

AU - Karnezis, Anthony N.

AU - Hudson-Price, Lisa

AU - Dhawan, Jyotsna

AU - Michalek, Joel E.

AU - Ciulli, Alessio

AU - Vakoc, Christopher R.

AU - Keller, Charles

PY - 2022/3/10

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N2 - 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.

AB - 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.

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SMARCA4 biology in alveolar rhabdomyosarcoma

Abstract

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