Characterization of Chronic Lymphocytic Leukemia Progression to Richter Transformation: Patient-derived xenograft models as an evolutionary model
[eng] Chronic lymphocytic leukemia (CLL) is a prevalent form of leukemia among adults in western countries, marked by a monoclonal mature CD19+ CD5+ B cell expansion in the peripheral blood, secondary lymphoid tissues, and bone marrow. In 5-10% of cases, it transforms into Richter transformation (RT...
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| Tipo de documento: | tese |
| Estado: | Versão publicada |
| Data de publicação: | 2024 |
| País: | España |
| Recursos: | Universidad de Barcelona |
| Repositório: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/211303 |
| Acesso em linha: | https://hdl.handle.net/2445/211303 http://hdl.handle.net/10803/690888 |
| Access Level: | Acceso aberto |
| Palavra-chave: | Oncologia Hematologia Immunologia Citometria de fluxe Oncology Hematology Immunology Flow cytometry |
| Resumo: | [eng] Chronic lymphocytic leukemia (CLL) is a prevalent form of leukemia among adults in western countries, marked by a monoclonal mature CD19+ CD5+ B cell expansion in the peripheral blood, secondary lymphoid tissues, and bone marrow. In 5-10% of cases, it transforms into Richter transformation (RT), a diffuse large B-cell lymphoma associated with a poor prognosis. However, the mechanisms responsible for driving RT are still not well understood. In this Thesis, we present novel insights into RT and a detailed development of two new patient-derived xenograft (PDX) models for RT. One of these models derived from a CLL sample, which accurately reflects the clinical transformation of CLL to RT observed in the patient's follow-up. In the first chapter, we analyzed 54 longitudinal samples using genomic, epigenomic and transcriptomic techniques that covered up to 19 years of disease progression. The genomic analysis revealed the early seeding of RT subclones that drive advanced stages of cancer evolution as early as 19 years before the final expansion. Furthermore, we identified new driver alterations and described a new transcriptional axis in RT with oxidative phosphorylation (OXPHOS)high – B-cell receptor (BCR)low signaling. The study demonstrated the effectiveness of inhibiting the proliferation of RT cells by targeting OXPHOS. In the second chapter, we established two new PDXs by injecting CLL (PDX12) and RT (PDX19) cells into immunocompromised NSG mice. Both PDXs exhibited similar morphological and phenotypic characteristics to those of RT. PDX progression analysis uncovered a genomic landscape similar to RT tumors from both patients and revealed unprecedented RT subclonal heterogeneity and clonal evolution during PDX generation. Transcriptomic analysis of PDXs demonstrated high OXPHOS and low BCR signaling that corresponded with RT levels in the patients. The OXPHOS inhibitor, IACS- 010759, decreased proliferation on these cells and circumvented resistance to venetoclax. |
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