Hereditary retinoblastoma iPSC model reveals aberrant spliceosome function driving bone malignancies.
Hereditary retinoblastoma iPSC model reveals aberrant spliceosome function driving bone malignancies.
复制标题
DOI：
10.1073/pnas.2117857119
复制
发表时间：
2022-04-19
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
罕见的人类遗传性疾病为基因突变在人类疾病发病机制中的作用提供了明确的证据，并为了解它们对人类疾病发展的影响提供了强有力的见解。利用遗传性视网膜母细胞瘤(RB)患者来源的诱导多能干细胞(IPSC)平台，我们阐明了PRB/E2F3a在调节剪接体基因表达中的作用。药物抑制RB1突变细胞中的剪接体优先增加参与促癌信号转导的基因的剪接异常，并损害细胞增殖和肿瘤的发生。PRb/E2F3a调节的剪接体蛋白的表达与pRb的表达呈负相关，并与骨肉瘤患者不良的临床预后相关。我们的发现有力地表明，剪接体是RB1突变OS的“阿喀琉斯之踵”。RB1基因在人类癌症中经常发生突变，但它在肿瘤发生中的作用仍未完全确定。利用遗传性视网膜母细胞瘤(RB)的诱导多能干细胞(IPSC)模型，我们报道了剪接体是RB1突变细胞中响应致癌压力的上调靶点。通过研究Rb iPSC来源的成骨细胞的转录本和基因组占有率，我们发现，介导剪接体基因表达的E2F3a和拮抗E2F3a的pRb都通过与剪接体基因的启动子或增强子共结合来共同调节超过三分之一的剪接体基因。药物抑制RB1突变细胞中的剪接体导致整体内含子保留，降低细胞增殖，并阻碍肿瘤的发生。肿瘤标本研究和全基因组TCGA(癌症基因组图谱)表达谱分析支持pRb和E2F3a在包括骨肉瘤(OS)在内的多种癌症类型中调节剪接体基因表达的临床相关性。高水平的pRb/E2F3a调节的剪接体基因与OS患者较差的存活率有关。总体而言，这些发现揭示了pRb、E2F3a、剪接体和肿瘤发生之间尚未发现的联系，表明剪接体机制可能是pRb缺陷癌症的一种潜在的广泛治疗脆弱性。
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. 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.
登录
查看更多内容
影响因子：
64.5
作者：
Lee DF;Su J;Kim HS;Chang B;Papatsenko D;Zhao R;Yuan Y;Gingold J;Xia W;Darr H;Mirzayans R;Hung MC;Schaniel C;Lemischka IR
通讯作者：
Lemischka IR
影响因子：
--
作者：
Ceron, Julian;Rual, Jean-Francois;Chandra, Abha;Dupuy, Denis;Vidal, Marc;van den Heuvel, Sander
通讯作者：
van den Heuvel, Sander
DOI：
10.1136/mp.55.6.389
发表时间：
2002-12-01
期刊：
JOURNAL OF CLINICAL PATHOLOGY-MOLECULAR PATHOLOGY
影响因子：
--
作者：
Batanian, JR;Cavalli, LR;Haddad, BR
通讯作者：
Haddad, BR
影响因子：
7.3
作者：
Cohen-Eliav, Michal;Golan-Gerstl, Regina;Karni, Rotem
通讯作者：
Karni, Rotem
DOI：
10.1073/pnas.1814044115
发表时间：
2018-11-20
影响因子：
11.1
作者：
Kim, Huensuk;Yoo, Seungyeul;Schaniel, Christoph
通讯作者：
Schaniel, Christoph