B-cell lymphomas represent a heterogeneous group of malignancies, with diffuse large B-cell lymphoma (DLBCL) being the most common and aggressive subtype. Aggressive B-cell lymphomas may arise de novo, through transformation from indolent lymphomas such as marginal zone lymphoma (MZL), or in specific clinical contexts such as post-transplant lymphoproliferative disorders (PTLD) and relapsed/refractory DLBCL (R/R DLBCL). This thesis investigates the biological mechanisms underlying lymphoma progression and transformation, and evaluates the utility of circulating tumor DNA (ctDNA) as a biomarker across various aggressive B-cell lymphoma subtypes.
Clinical and molecular analyses identified risk factors for MZL transformation and revealed that transformed MZL frequently acquires features of germinal center B cells. Multi-omics approaches showed only subtle genomic and transcriptomic changes during transformation. Across subtypes, ctDNA emerged as a promising non-invasive biomarker for diagnosis, prognosis, and disease monitoring. In PTLD, ctDNA profiling revealed recurrent genetic alterations and closely reflected tumor characteristics and guide treatment decisions.
In R/R DLBCL, a high ctDNA tumor fraction was associated with poor prognosis. Persistent ctDNA mutations or copy number alterations provided complementary diagnostic value when combined with PET-CT, supporting their integrated use in assessing disease progression and guiding treatment decisions.
Together, these findings underscore ctDNA as a clinically informative biomarker across aggressive B-cell lymphoma subtypes, with potential to improve risk stratification and therapeutic guidance.

Protein synthesis is an energy-intensive process, with translation initiation being a key regulatory step. This thesis focuses on the roles of three translation initiation factors in cancer with the aim to identify novel therapeutic targets.
Amplification of the chromosomal region encompassing the initiation factor 4EBP1 created a synthetic dependency on FGFR1 signaling in cancer. This indicates a therapeutic potential for FGFR1 inhibitors by effectively disrupting phosphorylation of 4EBP1. We showed that 4EBP1 plays a role in regulating genes involved in insulin signaling, glucose metabolism, and the inositol pathway, three pathways contributing to cancer progression.
Treatment of sarcomas with the 4EBP1 inhibitor CR-1-31B induced apoptosis and suppressed growth in vitro and in vivo. Ribosome profiling of cells treated with CR-1-31B identified YAP and TAZ as the critical eIF4A-dependent genes.
Inhibitors of the initiation factor eIF4A like silvestrol showed promising results in treating aggressive lymphomas. However, drug resistance arose through MDR1-mediated efflux of sivestrol. A genome-wide CRISPR/Cas9 screen revealed that activation of NRF2 reduced the efficacy of the eIF4A inhibitor. This resistance could be reverted by blocking FN3K which decreased the stability of NRF2.
Using pancreatic cancer models we showed that genes with long, structured 5’UTRs rely on eIF4A for translation. CR-1-31B treatment effectively suppressed tumor growth by disrupting KRAS-dependent translation, reducing KRAS, MYC, and ERK signaling.
In conclusion, our study demonstrates that disrupting translation initiation, particularly through 4EBP1 and eIF4A inhibition, can suppress tumor progression and this offers new therapeutic strategies for cancer.

This double-degree PhD research investigates two important human viruses, Epstein-Barr virus (EBV) and Hepatitis B virus (HBV), both of which establish lifelong persistent infections and are associated with cancer development. Using an interdisciplinary approach that integrates molecular profiling, functional assays, bioinformatics, and epidemiology, the research aims to understand how these viruses persist, evade immune surveillance, and contribute to chronic disease and cancer, providing insight into mechanisms of viral persistence and pathogenesis.

It examines EBV-encoded miRNAs in B cells and their role in EBV-driven B-cell lymphomas. These miRNAs regulate viral replication, latency programs, and infected B-cell survival by targeting viral and host transcripts. The miRNA profile of the largest EBV-positive classical Hodgkin lymphoma cohort was characterized and compared with EBV-positive Burkitt lymphoma, PTLD, and primary EBV infection controls. BHRF1 miRNAs were specific to PTLD, while BART miRNAs showed stable expression across groups. Highly expressed BART miRNAs were functionally validated, showing reduced cell growth or proliferation upon inhibition. GO analysis linked these miRNAs to apoptosis, proliferation, and cell cycle regulation.
The thesis also reviews occult HBV infection (OBI) in Latin America, highlighting limited and uneven prevalence data and underestimation due to reliance on serology. A study in northeast Colombia identified OBI in 1.1% of blood donors, underscoring limitations of serological screening and the need for DNA-based testing.

Overall, the dissertation highlights host–virus interactions driving EBV and HBV persistence and cancer risk, and supports improved diagnostic and preventive strategies.

Classic Hodgkin lymphoma (cHL) is a B-cell malignancy marked by Hodgkin and Reed/Sternberg (HRS) cells that highly express CD30. We explored the roles of microRNAs (miRNAs) in cHL pathogenesis and CD30-targeting therapy using Brentuximab Vedotin (BV) through high-throughput screening techniques. Review of miRNA-related studies on known and potential miRNA-target gene interactions identified multiple miRNA-gene pairs with potential relevance for cHL pathogenesis. This highlighted the relevance of miRNAs in cHL, warranting further studies to deepen our understanding.
A microRNA overexpression library screen revealed 11 miRNA-target gene pairs implicated in cHL pathogenesis and 66 miRNA constructs that regulate BV treatment response. Among these, miR-590 was found to inhibit CD30 expression and induce BV resistance. Additionally, miR-191-5p not only conferred BV resistance but also promoted cell growth. By using AGO2-immunoprecipitation, we identified a network of involved target genes, including PTEN.
To investigate endogenous miRNAs involved in BV resistance mechanisms, we established two BV-resistant cHL cell lines and observed dynamic changes in CD30 expression. Moreover, we utilized a miRNA-focused CRISPR-Cas9 screen to identify endogenous miRNAs that regulate CD30 expression and/or BV sensitivity. To this end, we generated two inducible Cas9 monoclonal cell lines and optimized the entire screening process. These screens await further data analysis.
In summary, this thesis highlights the functional importance of specific miRNAs in cHL and provides detailed procedures of the miRNA-focused screening approaches, from initial setup to optimization and validation of results.

Classic Hodgkin lymphoma (cHL) is a cancer of the immune system common in adolescents and young adults. The chance to develop cHL is strongly influenced by genetically defined human leukocyte antigen (HLA) types. The main function of HLA is to present antigenic peptides and it is a critical player in the normal immune system. In this thesis we focused on the mechanisms of HLA-related associations with cHL. First, we showed that part of the cHL-associated HLA alleles are associated with loss of HLA expression on tumour cells. Second, we identified novel ERAP – HLA interactions that were specific for cHL patients and not observed in controls. Together these data show that antigen presentation is a critical component in defining the susceptibility to develop cHL. Lastly, we identified an association between cHL and killer cell immunoglobulin-like receptors (KIRs). These KIRs interact with HLA class I molecules expressed on target cells and play an important role in clearance of virus-infected or tumour cells. We found that KIR haplotype B protects against the development of a specific cHL subgroup (EBV+ nodular sclerosis). In addition, we observed presence of KIR2DL2 – HLA-C1 and KIR2DS2 – HLA-C1 at significantly lower carrier frequencies in this cHL subgroup compared to controls. Overall, our studies showed that multiple HLA associated molecules influence susceptibility to develop cHL. The results of this thesis further support the critical role of HLA and antigen presentation in cHL susceptibility and extends on the biological mechanisms underlying the development of cHL.