Chronic lymphocytic leukemia patient-derived xenografts recapitulate clonal evolution to Richter transformation.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
28 Nov 2023
28 Nov 2023
Historique:
received:
13
06
2023
accepted:
15
11
2023
revised:
08
11
2023
medline:
29
11
2023
pubmed:
29
11
2023
entrez:
28
11
2023
Statut:
aheadofprint
Résumé
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.
Identifiants
pubmed: 38017105
doi: 10.1038/s41375-023-02095-5
pii: 10.1038/s41375-023-02095-5
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Ministry of Economy and Competitiveness | Agencia Estatal de Investigación (Spanish Agencia Estatal de Investigación)
ID : RTI2018-094584-B-I00
Organisme : Ministry of Economy and Competitiveness | Agencia Estatal de Investigación (Spanish Agencia Estatal de Investigación)
ID : PID2021-123165OB-I00
Organisme : American Association for Cancer Research (American Association for Cancer Research, Inc.)
ID : 21-40-11-NADE
Organisme : European Hematology Association (EHA)
ID : RG-202012-00245
Organisme : Lady Tata Memorial Trust
ID : LADY_TATA_21_3223
Informations de copyright
© 2023. The Author(s).
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