{"title":"细胞质脂滴可预测弥漫大 B 细胞淋巴瘤的不良预后:下一代测序解密脂肪生成基因。","authors":"Shu-Hsien Wang, Po-Min Chiang, Yung-Yeh Su, Yu-Ting Yu, Ya-Ping Chen, Tsai-Yun Chen, L Jeffrey Medeiros, Chang-Yao Chu, Peng-Chieh Chen, Kung-Chao Chang","doi":"10.1097/PAS.0000000000002280","DOIUrl":null,"url":null,"abstract":"<p><p>Burkitt lymphoma is characterized by high cell turnover and numerous cytoplasmic vacuoles that are demonstrated to be lipid droplets (LDs) decorated by adipophilin. By contrast, cytoplasmic vacuoles are variably observed in diffuse large B-cell lymphoma (DLBCL) and less well characterized. In this study, we first validated in DLBCL that cytoplasmic vacuoles are indeed LDs by Oil-red-O stain, Bodipy fluorescent stain, and electron microscopy. Second, in a cohort of DLBCL patients (n=52) we showed that LDs in effusional lymphoma cells were associated with a poorer prognosis ( P =0.029, log-rank test) and higher International Prognostic Index (IPI) score (94% vs. 66%, P =0.026) than those without. Moreover, using adipophilin as a surrogate marker for LDs, we found in another cohort of biopsy specimen (n=85) that expression of adipophilin by lymphoma cells predicted a poorer prognosis ( P =0.007, log-rank test) and higher IPI score (63% vs. 30%, P =0.005). In addition, whole exome sequencing of effusional DLBCL cells showed LD-positive DLBCL shared genetic features with the MCD ( MYD88 and CD79B mutations) subtype and highlighted OSBPL10 and CUBN as the most frequently mutated genes involved in lipogenesis. Whole transcriptome analysis by comparing effusional DLBCL cells with versus without LDs showed upregulation of EHHADH , SLC1A1 , CD96 , INPP4B , and RNF183 relevant for lymphoma lipogenesis and upregulation of epithelial-mesenchymal transition and KRAS signaling pathways. Higher expression of EHHADH and CD96 were validated in LD-positive clinical samples and LD-rich cell lines than LD-poor cells along with the known lipogenic gene, FASN . Our findings highlight the roles of LDs and adipophilin expression in DLBCL, suggest that these markers may predict prognosis and show that lipogenic genes may be potential therapeutic targets.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"1425-1438"},"PeriodicalIF":4.5000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Cytoplasmic Lipid Droplets Predict Worse Prognosis in Diffuse Large B-Cell Lymphoma: Next-Generation Sequencing Deciphering Lipogenic Genes.\",\"authors\":\"Shu-Hsien Wang, Po-Min Chiang, Yung-Yeh Su, Yu-Ting Yu, Ya-Ping Chen, Tsai-Yun Chen, L Jeffrey Medeiros, Chang-Yao Chu, Peng-Chieh Chen, Kung-Chao Chang\",\"doi\":\"10.1097/PAS.0000000000002280\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Burkitt lymphoma is characterized by high cell turnover and numerous cytoplasmic vacuoles that are demonstrated to be lipid droplets (LDs) decorated by adipophilin. By contrast, cytoplasmic vacuoles are variably observed in diffuse large B-cell lymphoma (DLBCL) and less well characterized. In this study, we first validated in DLBCL that cytoplasmic vacuoles are indeed LDs by Oil-red-O stain, Bodipy fluorescent stain, and electron microscopy. Second, in a cohort of DLBCL patients (n=52) we showed that LDs in effusional lymphoma cells were associated with a poorer prognosis ( P =0.029, log-rank test) and higher International Prognostic Index (IPI) score (94% vs. 66%, P =0.026) than those without. Moreover, using adipophilin as a surrogate marker for LDs, we found in another cohort of biopsy specimen (n=85) that expression of adipophilin by lymphoma cells predicted a poorer prognosis ( P =0.007, log-rank test) and higher IPI score (63% vs. 30%, P =0.005). In addition, whole exome sequencing of effusional DLBCL cells showed LD-positive DLBCL shared genetic features with the MCD ( MYD88 and CD79B mutations) subtype and highlighted OSBPL10 and CUBN as the most frequently mutated genes involved in lipogenesis. Whole transcriptome analysis by comparing effusional DLBCL cells with versus without LDs showed upregulation of EHHADH , SLC1A1 , CD96 , INPP4B , and RNF183 relevant for lymphoma lipogenesis and upregulation of epithelial-mesenchymal transition and KRAS signaling pathways. Higher expression of EHHADH and CD96 were validated in LD-positive clinical samples and LD-rich cell lines than LD-poor cells along with the known lipogenic gene, FASN . Our findings highlight the roles of LDs and adipophilin expression in DLBCL, suggest that these markers may predict prognosis and show that lipogenic genes may be potential therapeutic targets.</p>\",\"PeriodicalId\":7772,\"journal\":{\"name\":\"American Journal of Surgical Pathology\",\"volume\":\" \",\"pages\":\"1425-1438\"},\"PeriodicalIF\":4.5000,\"publicationDate\":\"2024-11-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American Journal of Surgical Pathology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1097/PAS.0000000000002280\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/7/9 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"PATHOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Surgical Pathology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/PAS.0000000000002280","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/9 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"PATHOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
伯基特淋巴瘤的特点是细胞新陈代谢旺盛,并有大量胞浆空泡,这些空泡被证明是由嗜脂蛋白装饰的脂滴(LD)。相比之下,细胞质空泡在弥漫大 B 细胞淋巴瘤(DLBCL)中的观察结果不尽相同,特征也不明显。在本研究中,我们首先通过Oil-red-O染色法、Bodipy荧光染色法和电子显微镜在DLBCL中验证了细胞质空泡确实是LDs。其次,在一组 DLBCL 患者(n=52)中,我们发现与无 LD 的患者相比,流出淋巴瘤细胞中的 LD 与较差的预后(P=0.029,log-rank 检验)和较高的国际预后指数(IPI)评分(94% vs. 66%,P=0.026)相关。此外,我们还利用嗜脂素作为低密度淋巴瘤的替代标记物,在另一批活检标本(n=85)中发现,淋巴瘤细胞表达嗜脂素预示着较差的预后(P=0.007,log-rank检验)和较高的IPI评分(63% vs. 30%,P=0.005)。此外,流出型DLBCL细胞的全外显子组测序显示,LD阳性DLBCL与MCD(MYD88和CD79B突变)亚型具有共同的遗传特征,并突出显示OSBPL10和CUBN是参与脂肪生成的最常见突变基因。通过比较有无LD的流出型DLBCL细胞,全转录组分析显示,与淋巴瘤脂肪生成相关的EHHADH、SLC1A1、CD96、INPP4B和RNF183上调,上皮-间质转化和KRAS信号通路上调。经验证,在LD阳性的临床样本和富含LD的细胞系中,EHHADH和CD96以及已知的脂肪生成基因FASN的表达高于贫LD细胞。我们的研究结果突显了LDs和嗜脂素表达在DLBCL中的作用,表明这些标志物可预测预后,并显示生脂基因可能是潜在的治疗靶点。
Cytoplasmic Lipid Droplets Predict Worse Prognosis in Diffuse Large B-Cell Lymphoma: Next-Generation Sequencing Deciphering Lipogenic Genes.
Burkitt lymphoma is characterized by high cell turnover and numerous cytoplasmic vacuoles that are demonstrated to be lipid droplets (LDs) decorated by adipophilin. By contrast, cytoplasmic vacuoles are variably observed in diffuse large B-cell lymphoma (DLBCL) and less well characterized. In this study, we first validated in DLBCL that cytoplasmic vacuoles are indeed LDs by Oil-red-O stain, Bodipy fluorescent stain, and electron microscopy. Second, in a cohort of DLBCL patients (n=52) we showed that LDs in effusional lymphoma cells were associated with a poorer prognosis ( P =0.029, log-rank test) and higher International Prognostic Index (IPI) score (94% vs. 66%, P =0.026) than those without. Moreover, using adipophilin as a surrogate marker for LDs, we found in another cohort of biopsy specimen (n=85) that expression of adipophilin by lymphoma cells predicted a poorer prognosis ( P =0.007, log-rank test) and higher IPI score (63% vs. 30%, P =0.005). In addition, whole exome sequencing of effusional DLBCL cells showed LD-positive DLBCL shared genetic features with the MCD ( MYD88 and CD79B mutations) subtype and highlighted OSBPL10 and CUBN as the most frequently mutated genes involved in lipogenesis. Whole transcriptome analysis by comparing effusional DLBCL cells with versus without LDs showed upregulation of EHHADH , SLC1A1 , CD96 , INPP4B , and RNF183 relevant for lymphoma lipogenesis and upregulation of epithelial-mesenchymal transition and KRAS signaling pathways. Higher expression of EHHADH and CD96 were validated in LD-positive clinical samples and LD-rich cell lines than LD-poor cells along with the known lipogenic gene, FASN . Our findings highlight the roles of LDs and adipophilin expression in DLBCL, suggest that these markers may predict prognosis and show that lipogenic genes may be potential therapeutic targets.
期刊介绍:
The American Journal of Surgical Pathology has achieved worldwide recognition for its outstanding coverage of the state of the art in human surgical pathology. In each monthly issue, experts present original articles, review articles, detailed case reports, and special features, enhanced by superb illustrations. Coverage encompasses technical methods, diagnostic aids, and frozen-section diagnosis, in addition to detailed pathologic studies of a wide range of disease entities.
Official Journal of The Arthur Purdy Stout Society of Surgical Pathologists and The Gastrointestinal Pathology Society.