BAF complexes drive proliferation and block myogenic differentiation in fusion-positive rhabdomyosarcoma

Dominik Laubscher, Berkley E. Gryder, Benjamin D. Sunkel, Thorkell Andresson, Marco Wachtel, Sudipto Das, Bernd Roschitzki, Witold Wolski, Xiaoli S. Wu, Hsien-Chao Chou, Young K. Song, Chaoyu Wang, Jun S. Wei, Meng Wang, Xinyu Wen, Quy Ai Ngo, Joana G. Marques, Christopher R. Vakoc, Beat W. Schäfer (), Benjamin Z. Stanton () and Javed Khan ()
Additional contact information
Dominik Laubscher: University Children’s Hospital
Berkley E. Gryder: Genetics Branch, NCI, NIH
Benjamin D. Sunkel: Center for Childhood Cancer and Blood Diseases
Thorkell Andresson: Frederick National Laboratory for Cancer Research
Marco Wachtel: University Children’s Hospital
Sudipto Das: Frederick National Laboratory for Cancer Research
Bernd Roschitzki: University of Zurich/ETH Zurich
Witold Wolski: University of Zurich/ETH Zurich
Xiaoli S. Wu: Cold Spring Harbor Laboratory
Hsien-Chao Chou: Genetics Branch, NCI, NIH
Young K. Song: Genetics Branch, NCI, NIH
Chaoyu Wang: Genetics Branch, NCI, NIH
Jun S. Wei: Genetics Branch, NCI, NIH
Meng Wang: Center for Childhood Cancer and Blood Diseases
Xinyu Wen: Genetics Branch, NCI, NIH
Quy Ai Ngo: University Children’s Hospital
Joana G. Marques: University Children’s Hospital
Christopher R. Vakoc: Cold Spring Harbor Laboratory
Beat W. Schäfer: University Children’s Hospital
Benjamin Z. Stanton: Center for Childhood Cancer and Blood Diseases
Javed Khan: Genetics Branch, NCI, NIH

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Rhabdomyosarcoma (RMS) is a pediatric malignancy of skeletal muscle lineage. The aggressive alveolar subtype is characterized by t(2;13) or t(1;13) translocations encoding for PAX3- or PAX7-FOXO1 chimeric transcription factors, respectively, and are referred to as fusion positive RMS (FP-RMS). The fusion gene alters the myogenic program and maintains the proliferative state while blocking terminal differentiation. Here, we investigated the contributions of chromatin regulatory complexes to FP-RMS tumor maintenance. We define the mSWI/SNF functional repertoire in FP-RMS. We find that SMARCA4 (encoding BRG1) is overexpressed in this malignancy compared to skeletal muscle and is essential for cell proliferation. Proteomic studies suggest proximity between PAX3-FOXO1 and BAF complexes, which is further supported by genome-wide binding profiles revealing enhancer colocalization of BAF with core regulatory transcription factors. Further, mSWI/SNF complexes localize to sites of de novo histone acetylation. Phenotypically, interference with mSWI/SNF complex function induces transcriptional activation of the skeletal muscle differentiation program associated with MYCN enhancer invasion at myogenic target genes, which is recapitulated by BRG1 targeting compounds. We conclude that inhibition of BRG1 overcomes the differentiation blockade of FP-RMS cells and may provide a therapeutic strategy for this lethal childhood tumor.

Date: 2021
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DOI: 10.1038/s41467-021-27176-w

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