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.

Richter 转化 (RT) 是慢性淋巴细胞性白血病 (CLL) 演变为非常具有侵袭性的大 B 细胞淋巴瘤的典型演变，导致预后不佳。驱动 RT 的机制在很大程度上仍然未知。我们对 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。研究涵盖长达 19 年病程的 54 个纵向样本，我们发现了携带已在 CLL 诊断时的 RT 细胞基因组、免疫遗传学和转录组学特征的微小亚克隆，这些亚克隆在转化前休眠长达 19 年。^{我们还发现了新的驱动程序改变，发现了新的突变特征 (SBS-RT)，发现了高}氧化磷酸化 (OXPHOS)-B 细胞受体 (BCR)在 RT 中的^低信号转录轴，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。