4.7 Article

Chronic lymphocytic leukemia patient-derived xenografts recapitulate clonal evolution to Richter transformation

期刊

LEUKEMIA
卷 -, 期 -, 页码 -

出版社

SPRINGERNATURE
DOI: 10.1038/s41375-023-02095-5

关键词

-

向作者/读者索取更多资源

This study established patient-derived xenograft models to investigate the molecular characteristics and evolution of chronic lymphocytic leukemia (CLL) and Richter transformation (RT). The models revealed the subclonal heterogeneity and clonal evolution of RT cells during PDX generation. Transcriptomic analysis showed high oxidative phosphorylation and low B-cell receptor signaling in RT, and an OXPHOS inhibitor circumvented drug resistance. The study provides valuable insights into the intrinsic features of RT cells.
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.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据