Hereditary retinoblastoma iPSC model reveals aberrant spliceosome function driving bone malignancies
Abstract
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 in RB1 -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” of RB1 -mutant OS.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 11, 2022
- Source ID
- 10.1073/pnas.2117857119
Entities
People
- An Xu
- Chad D. Huff
- Dandan Zhu
- Danielle Bazer
- Dung-Fang Lee
- Jason T Yustein
- Jian Tu
- Jie Su
- Jingnan Shen
- Julian Gingold
- Kuang-lei Tsai
- Lisa L. Wang
- Mien-Chie Hung
- Mo-Fan Huang
- Nicolas R. Forcioli-conti
- Peilin Jia
- Ruifeng Hu
- Ruiying Zhao
- Ruoyu Wang
- Sarah X. L. Huang
- Thomas R Webb
- Yi-hung Chen
- Yu Yao
- Zhongming Zhao
- Zijun Huo
Organizations
- Asia University
- Baylor College of Medicine
- Cancer Prevention and Research Institute of Texas
- China Medical University
- National Cancer Institute
- National Natural Science Foundation of China
- Stony Brook University
- Sun Yat-sen University
- United States Department of Defense
- United States National Library of Medicine
- University of Texas Health Science Center at Houston
- University of Texas at Austin