Abstract
The role of extracellular vesicles (EVs) proteome in diffuse large B-cell lymphoma (DLBCL) pathology, subclassification, and patient screening is unexplored. We analyzed by state-of-the-art mass spectrometry the whole cell and secreted extracellular vesicles (EVs) proteomes of different molecular subtypes of DLBCL, germinal center B cell (GCB subtype), and activated B cell (ABC subtype). After quality control assessment, we compared whole-cell and secreted EVs proteomes of the two cell-of-origin (COO) categories, GCB and ABC subtypes, resulting in 288/1115 significantly differential expressed proteins from the whole-cell proteome and 228/608 proteins from EVs (adjust p-value < 0.05/p-value < 0.05). In our preclinical model system, we demonstrated that the EV proteome and the whole-cell proteome possess the capacity to separate cell lines into ABC and GCB subtypes. KEGG functional analysis and GO enrichment analysis for cellular component, molecular function, and biological process of differential expressed proteins (DEP) between ABC and GCB EVs showed a significant enrichment of pathways involved in immune response function. Other enriched functional categories for DEPs constitute cellular signaling and intracellular trafficking such as B-cell receptor (BCR), Fc_gamma R-mediated phagocytosis, ErbB signaling, and endocytosis. Our results suggest EVs can be explored as a tool for patient diagnosis, follow-up, and disease monitoring. Finally, this study proposes novel drug targets based on highly expressed proteins, for which antitumor drugs are available suggesting potential combinatorial therapies for aggressive forms of DLBCL. Data are available via ProteomeXchange with identifier PXD028267.
Highlights
B-cell lymphomas develop from B-lymphocytes and account for 85% of all nonHodgkin lymphomas (NHLs)
Diffuse large B-cell lymphoma (DLBCL) is an aggressive form of NHL, infiltrating organs other than the lymph nodes at presentation in about 40% of the cases and with suboptimal outcomes in a fraction of patients
To explore the potential role of extracellular vesicles (EVs) proteome in the establishment of a signature to distinguish DLBCL subtypes based on cell of origin (COO), we have used established cell lines derived from patients annotated to DLBCL-GCB subtype (DB and HT) and activated B-cell like (ABC) subtype (RIVA and OCI-Ly3)
Summary
B-cell lymphomas develop from B-lymphocytes and account for 85% of all nonHodgkin lymphomas (NHLs). Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma, accounting for 25% to 30% of all newly diagnosed cases of NHL. DLBCL is an aggressive form of NHL, infiltrating organs other than the lymph nodes at presentation in about 40% of the cases and with suboptimal outcomes in a fraction of patients. Some DLBCL subtypes are defined by organ location and have particular biological characteristics. GEP of DLBCL revealed two main subtypes: GCB (germinal center B-cell like) and non-GCB. Non-GCB tumors include the unclassifiable and the activated B-cell like (ABC) DLBCL subtypes; the latter is associated with poor treatment outcomes [2,3]. A rarer primary mediastinal B-cell type was identified by GEP
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