Abstract
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.
Overview
- The study aimed to establish patient-derived xenograft (PDX) models to study the molecular features and evolution of chronic lymphocytic leukemia (CLL) and Richter transformation (RT).
- Two PDXs were generated 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. The primary objective of the study was to generate new RT-PDX models to uncover intrinsic features of RT cells of therapeutical value.
Comparative Analysis & Findings
- The study compared the outcomes observed under different experimental conditions or interventions detailed in the study. The results showed that 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. The key findings of the study were that the PDX models established in this study mimicked the evolution of CLL to RT and uncovered intrinsic features of RT cells of therapeutical value.
Implications and Future Directions
- The study's findings have significant implications for the field of research or clinical practice. The generated RT-PDX models can be used to study the molecular mechanisms of RT and to develop new therapeutic strategies. The study identified an unprecedented RT subclonal heterogeneity and clonal evolution during PDX generation, which can be used to study the evolution of RT and to develop personalized treatment strategies. The study also identified IACS-010759 as an effective OXPHOS inhibitor that can be used to treat RT. Future research directions could include studying the role of OXPHOS in RT and developing new OXPHOS inhibitors.