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慢性淋巴细胞白血病Richter转化的早期检测
作者:小柯机器人 发布时间:2022/8/13 23:50:58

西班牙巴塞罗那大学Elías Campo和西班牙马德里肿瘤生物研究中心Ferran Nadeu团队共同合作近期取得重要工作进展。他们研究开发了慢性淋巴细胞白血病Richter转化的早期检测方法。相关论文2022年8月11日在线发表于《自然—医学》杂志上。

研究人员对19例发生RT的CLL病例的全基因组、表观基因组和转录组进行了表征,并结合单细胞DNA/RNA测序分析和功能实验。通过研究涵盖长达19年病程的54个纵向样本,研究人员发现了在CLL诊断时已经携带RT细胞的基因组、免疫遗传学和转录组特征的微小亚克隆,这些亚克隆在转化前休眠长达19年。他们还发现了新的驱动改变,发现了一个新的突变特征(SBS-RT),识别了RT中的氧化磷酸化(OXPHOS)highB细胞受体(BCR)Low信号转录轴,并表明OXPHOS抑制降低了RT细胞的增殖。这些发现证明了亚克隆的早期播种推动了癌症进化的晚期阶段,并揭示了RT的潜在治疗靶点。

据介绍,Richter转化(RT)是慢性淋巴细胞白血病(CLL)向侵袭性大B细胞淋巴瘤的典型演变,预后不佳。驱动RT的机制在很大程度上仍是未知的。

附:英文原文

Title: Detection of early seeding of Richter transformation in chronic lymphocytic leukemia

Author: Nadeu, Ferran, Royo, Romina, Massoni-Badosa, Ramon, Playa-Albinyana, Heribert, Garcia-Torre, Beatriz, Duran-Ferrer, Mart, Dawson, Kevin J., Kulis, Marta, Diaz-Navarro, Ander, Villamor, Neus, Melero, Juan L., Chapaprieta, Vicente, Dueso-Barroso, Ana, Delgado, Julio, Moia, Riccardo, Ruiz-Gil, Sara, Marchese, Domenica, Gir, Ariadna, Verdaguer-Dot, Nria, Romo, Mnica, Clot, Guillem, Rozman, Maria, Frigola, Gerard, Rivas-Delgado, Alfredo, Baumann, Tycho, Alcoceba, Miguel, Gonzlez, Marcos, Climent, Fina, Abrisqueta, Pau, Castellv, Josep, Bosch, Francesc, Aymerich, Marta, Enjuanes, Anna, Ruiz-Gasp, Slvia, Lpez-Guillermo, Armando, Jares, Pedro, Be, Slvia, Capella-Gutierrez, Salvador, Gelp, Josep Ll., Lpez-Bigas, Nria, Torrents, David, Campbell, Peter J., Gut, Ivo, Rossi, Davide, Gaidano, Gianluca, Puente, Xose S., Garcia-Roves, Pablo M., Colomer, Dolors, Heyn, Holger, Maura, Francesco, Martn-Subero, Jos I., Campo, Elas

Issue&Volume: 2022-08-11

Abstract: Richter transformation (RT) is a paradigmatic evolution of chronic lymphocytic leukemia (CLL) into a very aggressive large B cell lymphoma conferring a dismal prognosis. The mechanisms driving RT remain largely unknown. We characterized the whole genome, epigenome and transcriptome, combined with single-cell DNA/RNA-sequencing analyses and functional experiments, of 19 cases of CLL developing RT. Studying 54 longitudinal samples covering up to 19 years of disease course, we uncovered minute subclones carrying genomic, immunogenetic and transcriptomic features of RT cells already at CLL diagnosis, which were dormant for up to 19 years before transformation. We also identified new driver alterations, discovered a new mutational signature (SBS-RT), recognized an oxidative phosphorylation (OXPHOS)high–B cell receptor (BCR)low-signaling transcriptional axis in RT and showed that OXPHOS inhibition reduces the proliferation of RT cells. These findings demonstrate the early seeding of subclones driving advanced stages of cancer evolution and uncover potential therapeutic targets for RT.

DOI: 10.1038/s41591-022-01927-8

Source: https://www.nature.com/articles/s41591-022-01927-8

 

期刊信息

Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:30.641
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex