Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
Nat Med. 2022 Aug;28(8):1662-1671. doi: 10.1038/s41591-022-01927-8. Epub 2022 Aug 11.
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)-B cell receptor (BCR)-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.
里希特转化（RT）是慢性淋巴细胞白血病（CLL）向非常侵袭性的大 B 细胞淋巴瘤的典型演变，预后不良。驱动 RT 的机制在很大程度上尚不清楚。我们对 19 例发生 RT 的 CLL 进行了全基因组、表观基因组和转录组的特征分析，结合单细胞 DNA/RNA 测序分析和功能实验。研究了长达 19 年疾病过程的 54 个纵向样本，我们发现微小亚克隆在 CLL 诊断时就已经携带 RT 细胞的基因组、免疫遗传学和转录组特征，在转化前长达 19 年处于休眠状态。我们还发现了新的驱动改变，发现了一个新的突变特征（SBS-RT），在 RT 中识别出氧化磷酸化（OXPHOS）-B 细胞受体（BCR）-信号转导转录轴，并表明 OXPHOS 抑制可降低 RT 细胞的增殖。这些发现表明，亚克隆的早期播种驱动癌症进化的晚期阶段，并揭示了 RT 的潜在治疗靶点。
