Diffuse large B-cell lymphoma (DLBCL) is the most common histological subtype of non-Hodgkin’s lymphomas. DLBCL is an aggressive malignancy that displays major heterogeneity in terms of morphology, genetics and biological behavior. While complete remission is obtained in 70% of cases, patients with refractory or relapsed disease have a poor prognosis. Current classifications fail to identify high-risk subgroups and improve their outcomes. In this project, in-depth RNA profiling is performed on matched tissue and plasma samples within a large human DLBCL cohort to identify biomarkers that are linked to phenotype, therapy response and prognosis. Patient samples have been collected at diagnosis, during therapy, and follow-up. Secondly, longitudinal cell-free RNA (cfRNA) expression is explored within a DLBCL patient-derived tumor xenograft model. This unique, complementary design enables step-by-step dissection of the circulating transcriptome by characterizing tumor-, immune-, and stromal-derived fractions, as well as their reciprocal relation in a controlled setting. The total sequencing approach provides an unbiased exploration of all RNA classes, including long and circular non-coding RNA, and of the microenvironment through computational deconvolution. Lastly, value of cfRNA will be compared with cfDNA and methylation patterns in a multi-omics analysis. This study aims to push the liquid biopsy field further forward, contributing to the realisation of personalized medicine.