Proteogenomic characterization of diffuse large B-cell lymphoma

• Applicants: Professor Dr. Florian Buettner, Ph.D.; Professor Dr. Thomas Oellerich; Dr. Kuan-Ting Pan, Ph.D.
• Subject Area: Hematology, Oncology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 496906589

Diffuse large B cell lymphoma (DLBCL) is the most common type of aggressive Non-Hodgkin lymphomas. Gene expression profiling classified the heterogeneous disease into distinct subtypes with varied clinical outcomes. More recent studies revealed marked differences in their genomic profiles and identified a total of six genetic DLBCL subtypes each characterized by specific mutation profiles. However, the functional consequences of these genetic aberrations on the cellular proteome and drug response of DLBCL remain largely elusive. In recent years, the constant improvement of proteomic techniques has paved the way for very deep quantitative profiling of cellular proteomes and post-translational modifications (PTM), making it possible to elucidate the molecular pathophysiology of cancer beyond mere genomics, and to systematically define proteogenomic disease subtypes and biomarkers with clinical relevance. However, the proteomic landscape of DLBCL remains unexplored. Here, we propose applying our established proteomic pipeline to characterize, at a systems level, the proteome, N-glycoproteome, and phosphoproteome of a large representative population-based DLBCL patient cohort with detailed genomic and clinical information (n = 500) (Aim 1). This first large-scale (phospho/glyco)proteome profiling of DLBCLs will significantly enhance our understanding of proteomic and signaling characteristics in DLBCL and has high potential for biomarker discovery, for example for the identification of high-risk DLBCL subgroups. To this end, we will apply and further develop our multi-omics data analysis algorithms to identify proteomic and proteogenomic DLBCL subgroups and discover predictive molecular signatures for improved DLBCL stratification and diagnosis (Aim 2). Finally, we aim to functionally elucidate so far undescribed pathomechanisms in DLBCL models with a specific focus on the largely unexplored DLBCL glycoproteome (Aim 3). To this end, we will integrate our functional genomic data from CRISPR-Cas9 screens in more than 10 DLBCL cell lines to identify vulnerabilities in the identified DLBCL subtypes. A specific focus will be – in addition to candidates identified in our proteogenomic analysis – on MGAT1, encoding an enzyme that initiates complex-type N-glycans synthesis, since we identified this enzyme as a DLBCL-specific vulnerability. The proposed comprehensive proteome and PTMs characterization of our representative DLBCL cohort and the multi-omics data analysis will identify i) the proteogenomic DLBCL subtypes and their clinical characteristics, ii) biomarkers predictive for therapy response, and iii) undescribed pathomechanisms linked to proteogenomic aberrations. Our ultimate goal is to improve the molecular stratification of DLBCL and to identify relevant pathomechanisms that would provide a basis for innovative therapeutic approaches.

• DFG Programme: Research Grants
• International Connection: United Kingdom, USA
• Cooperation Partners: Professor Dr. Louis Staudt, Ph.D.; Professor Reuben Tooze