2026-04-17T10:51:18Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/2243222025-12-04T19:09:01Zcom_2072_1057col_2072_478858col_2072_478916col_2072_478917col_2072_478921

00925njm 22002777a 4500 dc Playa-Albinyana, Heribert author Arenas Ríos, Fabián author Royo, Romina author Giró, Ariadna author López Oreja, Irene author Aymerich, Marta author López Guerra, Mónica author Frigola, Gerard author Beà Bobet, Sílvia M. author Delgado, Julio (Delgado González) author Garcia-Roves, Pablo M. author Campo Güerri, Elias author Nadeu Prat, Ferran author Colomer Pujol, Dolors author 2025-11-12T16:23:25Z 2025-11-12T16:23:25Z 2023-11-28 2025-11-12T16:23:25Z 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 Patologia Limfomes Leucèmia Cèl·lules B Genètica Pathology Lymphomas Leukemia B cells Genetics Chronic lymphocytic leukemia patient-derived xenografts recapitulate clonal evolution to Richter transformation