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Hereditary retinoblastoma iPSC model reveals aberrant spliceosome function driving bone malignancies

The RB1 gene is frequently mutated in human cancers but its role in tumorigenesis remains incompletely defined. Using an induced pluripotent stem cell (iPSC) model of hereditary retinoblastoma (RB), we report that the spliceosome is an up-regulated target responding to oncogenic stress in RB1-mutant...

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Detalles Bibliográficos
Autores principales: Tu, Jian, Huo, Zijun, Yu, Yao, Zhu, Dandan, Xu, An, Huang, Mo-Fan, Hu, Ruifeng, Wang, Ruoyu, Gingold, Julian A., Chen, Yi-Hung, Tsai, Kuang-Lei, Forcioli-Conti, Nicolas R., Huang, Sarah X. L., Webb, Thomas R., Su, Jie, Bazer, Danielle A., Jia, Peilin, Yustein, Jason T., Wang, Lisa L., Hung, Mien-Chie, Zhao, Zhongming, Huff, Chad D., Shen, Jingnan, Zhao, Ruiying, Lee, Dung-Fang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9169787/
https://www.ncbi.nlm.nih.gov/pubmed/35412907
http://dx.doi.org/10.1073/pnas.2117857119
Descripción
Sumario:The RB1 gene is frequently mutated in human cancers but its role in tumorigenesis remains incompletely defined. Using an induced pluripotent stem cell (iPSC) model of hereditary retinoblastoma (RB), we report that the spliceosome is an up-regulated target responding to oncogenic stress in RB1-mutant cells. By investigating transcriptomes and genome occupancies in RB iPSC–derived osteoblasts (OBs), we discover that both E2F3a, which mediates spliceosomal gene expression, and pRB, which antagonizes E2F3a, coregulate more than one-third of spliceosomal genes by cobinding to their promoters or enhancers. Pharmacological inhibition of the spliceosome in RB1-mutant cells leads to global intron retention, decreased cell proliferation, and impaired tumorigenesis. Tumor specimen studies and genome-wide TCGA (The Cancer Genome Atlas) expression profile analyses support the clinical relevance of pRB and E2F3a in modulating spliceosomal gene expression in multiple cancer types including osteosarcoma (OS). High levels of pRB/E2F3a–regulated spliceosomal genes are associated with poor OS patient survival. Collectively, these findings reveal an undiscovered connection between pRB, E2F3a, the spliceosome, and tumorigenesis, pointing to the spliceosomal machinery as a potentially widespread therapeutic vulnerability of pRB-deficient cancers.