Defining the specific features of human thymic B cell subsets, their relationship to primary mediastinal B cell lymphoma and nodular sclerosis Hodgkin lymphoma, and pathogenetic mechanisms in these lymphomas

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The thymus contains a small population of mature B cells. There is indication from studies in the mouse that these cells have an important role in T cell selection. However, only very little is known about their specific features and functions, and their relationship to conventional peripheral blood B cells in the human. Moreover, thymic B cells are considered as the cell of origin of primary mediastinal B cell lymphoma (PMBCL), and are also discussed as the origin of nodular sclerosis Hodgkin lymphoma (NS-HL) in young adults. But again, molecular studies to clarify the relationship between thymic B cells and the two types of lymphomas are missing. We hypothesize that human thymic B cells represent distinct B cell subsets with unique features and that they represent the cellular origin of PMBCL and NS-HL of young adults. In preparatory work, we identified four subsets of thymic B cells by flow cytometry (cells with the phenotype of naive B cells, IgM memory B cells, class-switched B cells and rare CD30+ B cells). We aim to determine the differentiation stage, clonal composition and intersubset relationship of these thymic B cell subsets by detailed analysis of their B cell receptor repertoire by amplicon next generation sequencing. We plan to comprehensively characterize their specific gene expression pattern in comparison to conventional naive and memory B cells through a transcriptome analysis by RNA sequencing. With this, we aim to obtain insight into the specific immunological features of thymic B cells. By comparison of the gene expression pattern of thymic B cells and isolated tumor cells of PMBCL and NS-HL we will determine the relationship between the normal and malignant cells as a means to clarify whether thymic B cells are the origin of the two types of lymphomas and identify deregulated genes in the lymphoma cells. We will also mine the RNA sequencing data of the lymphomas for mutations and fusion transcripts to identify novel genetic lesions. For selected deregulated or mutated genes we will perform functional studies on lymphoma cell lines to clarify the pathogenetic role of these events. Overall, we aim to perform the first comprehensive characterization of the still enigmatic human thymic B cells, clarify whether PMBCL and NS-HL in young adults are derived from thymic B cells, determine deregulated gene expression in these lymphomas, and reveal novel pathogenetic mechanisms in PMBCL and NS-HL.