Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Barcelona, Spain.
Leukemia. 2024 Mar;38(3):557-569. doi: 10.1038/s41375-023-02095-5. Epub 2023 Nov 28.
Chronic lymphocytic leukemia (CLL) is a B-cell neoplasm with a heterogeneous clinical behavior. In 5-10% of patients the disease transforms into a diffuse large-B cell lymphoma known as Richter transformation (RT), which is associated with dismal prognosis. Here, we aimed to establish patient-derived xenograft (PDX) models to study the molecular features and evolution of CLL and RT. We generated two PDXs by injecting CLL (PDX12) and RT (PDX19) cells into immunocompromised NSG mice. Both PDXs were morphologically and phenotypically similar to RT. Whole-genome sequencing analysis at different time points of the PDX evolution revealed a genomic landscape similar to RT tumors from both patients and uncovered an unprecedented RT subclonal heterogeneity and clonal evolution during PDX generation. In PDX12, the transformed cells expanded from a very small subclone already present at the CLL stage. Transcriptomic analysis of PDXs showed a high oxidative phosphorylation (OXPHOS) and low B-cell receptor (BCR) signaling similar to the RT in the patients. IACS-010759, an OXPHOS inhibitor, reduced proliferation, and circumvented resistance to venetoclax. In summary, we have generated new RT-PDX models, one of them from CLL cells that mimicked the evolution of CLL to RT uncovering intrinsic features of RT cells of therapeutical value.
慢性淋巴细胞白血病（CLL）是一种具有异质性临床行为的 B 细胞肿瘤。在 5-10%的患者中，该疾病会转化为弥漫性大 B 细胞淋巴瘤，称为里希特转化（RT），其预后不良。在这里，我们旨在建立患者来源的异种移植（PDX）模型，以研究 CLL 和 RT 的分子特征和演变。我们通过将 CLL（PDX12）和 RT（PDX19）细胞注入免疫缺陷的 NSG 小鼠中，生成了两个 PDX。这两个 PDX 在形态和表型上均与 RT 相似。在 PDX 进化的不同时间点进行全基因组测序分析揭示了与来自患者的 RT 肿瘤相似的基因组景观，并揭示了在 PDX 生成过程中前所未有的 RT 亚克隆异质性和克隆演变。在 PDX12 中，转化细胞从 CLL 阶段已经存在的非常小的亚克隆中扩增。PDX 的转录组分析显示，与患者中的 RT 相似，存在高氧化磷酸化（OXPHOS）和低 B 细胞受体（BCR）信号。IACS-010759，一种 OXPHOS 抑制剂，可降低增殖并规避对 venetoclax 的耐药性。总之，我们已经生成了新的 RT-PDX 模型，其中一个来自 CLL 细胞，模拟了 CLL 向 RT 的演变，揭示了具有治疗价值的 RT 细胞的内在特征。
