Open AccessHereditary retinoblastoma iPSC model reveals aberrant spliceosome function driving bone malignancies
Author(s) -
Jian Tu,
Zijun Huo,
Yao Yu,
Dandan Zhu,
An Xu,
Mo-Fan Huang,
Ruifeng Hu,
Ruo–Yu Wang,
Julian A. Gingold,
YiHung Chen,
KuangLei Tsai,
Nicolas R. Forcioli-Conti,
Sarah X.L. Huang,
Thomas R. Webb,
Jie Su,
Danielle Bazer,
Peilin Jia,
Jason T. Yustein,
Lisa L. Wang,
MienChie Hung,
Zhongming Zhao,
Chad Huff,
Jingnan Shen,
Ruiying Zhao,
DungFang Lee
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2117857119
Subject(s) - spliceosome , biology , carcinogenesis , induced pluripotent stem cell , genetics , cancer research , retinoblastoma , enhancer , gene , gene expression , rna splicing , rna , embryonic stem cell
Significance Rare human hereditary disorders provide unequivocal evidence of the role of gene mutations in human disease pathogenesis and offer powerful insights into their influence on human disease development. Using a hereditary retinoblastoma (RB) patient–derived induced pluripotent stem cell (iPSC) platform, we elucidate the role of pRB/E2F3a in regulating spliceosomal gene expression. Pharmacological inhibition of the spliceosome inRB1 -mutant cells preferentially increases splicing abnormalities of genes involved in cancer-promoting signaling and impairs cell proliferation and tumorigenesis. Expression of pRB/E2F3a–regulated spliceosomal proteins is negatively associated with pRB expression and correlates with poor clinical outcomes of osteosarcoma (OS) patients. Our findings strongly indicate that the spliceosome is an “Achilles’ heel” ofRB1 -mutant OS.