Integrative Chromatin Profiling in Mature B cell Lymphomas: Biological and Clinical Insights
[eng] The DNA molecule carries all the genetic information necessary for the development of living organisms. DNA is compacted in nucleus of human cells, wrapped around the nucleosome, a core of proteins called histones. The organization of the nucleosomes along the DNA molecules and the post transl...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/214643 |
| Acceso en línea: | https://hdl.handle.net/2445/214643 http://hdl.handle.net/10803/691816 |
| Access Level: | acceso abierto |
| Palabra clave: | Epigenètica Factors de transcripció Limfomes Epigenetics Transcription factors Cromatina Chromatin Lymphomas |
| Sumario: | [eng] The DNA molecule carries all the genetic information necessary for the development of living organisms. DNA is compacted in nucleus of human cells, wrapped around the nucleosome, a core of proteins called histones. The organization of the nucleosomes along the DNA molecules and the post translational modifications that histones may have, can influence gene expression. Study of epigenetic marks, such as DNA accessibility and histone modifications, can expand our knowledge on the biology of certain diseases such as lymphomas. In this doctoral thesis, different histone marks, chromatin accessibility and transcriptomics have been integrated to characterize the role of the chromatin modulation in the biology of mantle cell lymphoma (MCL) and Richter transformation (RT) of chronic lymphocytic leukaemia (CLL). I initially generated 10 MCL reference epigenomes that include six histone modifications, chromatin accessibility and gene expression (Study 1). An integrative analysis of these epigenomic layers revealed an MCL-specific chromatin signature as compared to normal B cells. The de novo active regulatory regions identified were linked to a set of genes related to cell development and activation. The two described MCL subtypes, conventional (cMCL) and the leukemic non-nodal MCL (nnMCL), show biological, genetic, transcriptomic, and clinical differences. I observed that they also present differences at the chromatin level. The analysis of cMCL specific regulatory regions revealed an enrichment in specific transcription factor families responsible for transcription regulation of genes involved in proliferation and carcinogenesis (i.e. Krüppel-related, ETS-related, BHLH-ZIP, Jun-related, E2F, and CEBP-related TF families). On the contrary, nnMCL did not show major changes in chromatin activation as compared to cMCL, showing relatively minor differences to normal B cells. Moreover, I identified that the different levels of chromatin activation among cMCL samples are related to clinical behaviour, with more activation associated with shorter overall survival (Study 2). Furthermore, chromatin analyses were integrated with genome and transcriptome to characterized Richter transformation (RT), an aggressive evolution of CLL into an aggressive large B cell lymphoma. We found small subclones carrying genomic, and transcriptomic features of RT cells already at CLL diagnosis, which were dormant for up to 19 years before transformation. We also identified new driver alterations and discovered a new mutational signature (SBS-RT). Analysing the chromatin landscape, I identified patterns of both chromatin activation (H3K27ac) and chromatin accessibility (ATAC-seq) unique for RT. Integration of epigenetics and transcriptomics revealed an oxidative phosphorylation (OXPHOS)high–B cell receptor (BCR)low-signalling transcriptional axis in RT, which has potential therapeutic implications (Study 3). In summary, this doctoral thesis provides significant insights into the role of the chromatin landscape in the biology of mature B cell lymphomas, showing that chromatin activation is linked to disease aggressiveness. |
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