Oncogenes in aggressive B cell lymphomas: dissecting the mechanisms of their aberrant expression and tumorigenic role
[eng] B cell lymphomas are a heterogeneous group of hematological neoplasms. The first tumorigenic events in B cell lymphomagenesis are usually translocations involving defined oncogenes that often lead a block on normal B cell differentiation. However, pre- tumoral cells need secondary hits involvi...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/222981 |
| Acceso en línea: | https://hdl.handle.net/2445/222981 http://hdl.handle.net/10803/695167 |
| Access Level: | acceso abierto |
| Palabra clave: | Limfomes Oncogens Lymphomas Oncogenes |
| Sumario: | [eng] B cell lymphomas are a heterogeneous group of hematological neoplasms. The first tumorigenic events in B cell lymphomagenesis are usually translocations involving defined oncogenes that often lead a block on normal B cell differentiation. However, pre- tumoral cells need secondary hits involving other oncogenes to progress. The principal aims of this Thesis were to explore the functional role of specific oncogenes in aggressive B cell lymphomas, as well as to unravel the mechanisms that underlie their aberrant expression in lymphoid malignancies. Our final aim was to identify more effective targeted therapies against new specific oncogenic pathways to improve the outcome and life quality of patients with aggressive lymphomas. In the Study 1 of this thesis, I focused on mantle cell lymphoma (MCL), one of the most aggressive mature B cell neoplasms. Two subgroups of the disease with distinct clinical, biological and molecular features have been described. SOX11 transcription factor is aberrantly overexpressed in conventional MCL (cMCL) and negative or very weakly expressed in the nnMCL subtype. SOX11 has an oncogenic role in the pathogenesis of MCL. Patients with MCL expressing the SOX11 transcription factor have been shown to have worse prognoses compared to those that do not express SOX11, likely due to shorter responses to treatment and a higher incidence of relapse to current therapies. This might be attributed to the role of SOX11 regulating progenitors and stem cells proliferation and differentiation in various tissues. Additionally, SOX11 has been shown to enhance cancer stem cell (CSC) properties and to promote drug resistance in several cancer cell types. Thus, the aims for Study 1 were to identify SOX11-dependent stemness-related factors as possible prognostic biomarkers for relapsed MCL, and to find therapeutic interventions targeting CSC-related genes for treatment of aggressive MCL. In Study 1, I found that SOX11+ MCLs showed enrichment of hematopoietic and leukemic stem cell-related gene signatures, compared to SOX11- MCL primary cases and cell lines. Moreover, I identified Musashi-2 (MSI2) RNA-binding protein as one of the most significant stem cell-related genes upregulated in SOX11+ MCLs compared to SOX11- MCLs. MSI2 expression correlated with worse overall survival in MCL. In addition, MSI2 expression was directly regulated by SOX11, and was associated with active intronic superenhancers. MSI2 upregulation might contribute to the maintenance of stem cell properties in MCL cells by promoting translation of stemness-related genes and downregulating apoptotic factors, since MSI2 knockdown and inhibition with Ro 08- 2750 (RO) small molecule impaired self-renewal capabilities, such as clonogenic growth and aldehyde dehydrogenase (ALDH) activity, and decreased cell survival and chemoresistance. Finally, MSI2 knockdown inhibited tumoral cell dissemination and growth in MCL xenotransplanted mice models. Unfortunately, RO showed toxicity in our MCL mouse model, impairing us to test the efficacy of MSI2 inhibition in vivo. Therefore, our results open a new perspective for treatment, highlighting MSI2 oncogene as a potential therapeutic target to inhibit drug resistance and relapse in aggressive MCLs. In the Study 2 of this thesis, I focused on Burkitt lymphoma (BL), a highly proliferative B cell neoplasm that originates from germinal center B cells. Three clinical variants are distinguished: endemic (eBL), sporadic (sBL) and immunodeficiency-related BL. eBL is usually positive for Epstein-Barr virus (EBV) infection and presents with jaw or facial bone involvement. sBL shows lower frequency of EBV infection, and usually involves abdomen (Peyer’s patches). One of the genetic hallmarks of BL is the t(8;14), leading to MYC overexpression. However, MYC overexpression is not enough to develop a BL. Several studies have revealed genetic and molecular differences depending on the clinical variant and the EBV status of BL patients. For instance, EBV+ BLs show lower driver mutations than EBV- BLs. Approximately 25-50% of BL patients show SOX11 overexpression. Although SOX11 has an impact on MCL prognosis, no association between SOX11 expression and survival has been found in BL. Several studies have shown the oncogenic role of SOX11 in the pathogenesis of MCL, but the contribution of SOX11 to BL pathogenesis and clinical evolution remains unknown. Thus, the aims for the Study 2 were to understand the clinical relevance of SOX11 expression in BL, and to shed light on the functional role of SOX11 in the development of BL. In Study 2, I have observed that EBV infection and SOX11 expression were mutually exclusive, and that SOX11+ BLs mainly exhibited IG-MYC translocations acquired during class switch recombination (CSR), rather than somatic hypermutation (SHM), the process predominantly observed in SOX11- and EBV+ BL cases. In addition, SOX11+ BLs showed lower levels of BCL6 and AICDA, alongside a distinct mutational landscape characterized by a higher frequency of SMARCA4, ID3 and RFX7 mutations, and a lower frequency of mutations in DDX3X gene, compared to EBV+ and SOX11- BLs. The previously described SOX11 distal enhancer regions associated to SOX11 expression in MCL were not observed in BL. There were similarities in the transcriptional program regulated by SOX11 in BL and MCL, including upregulation of chemokine receptors. However, SOX11+ BL cells did not show differences in tumor cell migration or adhesion towards stromal cells compared to SOX11- BL cell lines. Instead, BL SOX11+ cells showed more adhesion to VCAM-1, associated to homing through the Peyer’s patches. Therefore, I hypothesize that BL transformation could take place at different stages during germinal center differentiation and by distinct pathogenic mechanisms according to SOX11 expression or EBV infection in BLs. The molecular dichotomy observed between SOX11 and EBV suggests that both might play a role in early stages of BL tumorigenic transformation. However, due to limited functional effects observed upon ectopic overexpression of SOX11 in our BL cell line models compared to SOX11- BL cells, I hypothesize that SOX11 might not have a key role in the maintenance of this lymphoma in later stages. Overall, I have described the role of two oncogenes, MSI2 and SOX11, in two non-Hodgkin lymphomas, MCL and BL, respectively. I have unraveled the mechanisms by which MSI2 is overexpressed and how exerts its tumorigenic function in MCL, highlighting MSI2 as a new possible target for therapeutic interventions to overcome drug resistance in aggressive MCL. I have also given some insights into the functional role of SOX11 in BL, demonstrating a clear dichotomy between EBV and SOX11, and suggesting different B cell of origin and pathogenic mechanisms between them in the pathogenic early transformation of mature B cells in BL. These findings have improved our understanding of the molecular mechanisms underlying these lymphomas and might guide the development of future therapies. |
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