The FOX and the mutants in mature human B cells and DLBCL: The role of FOXP1 in mature human B cell biology and lymphomagenesis & prevalence of oncogenic MyD88 and CD79B mutations in diffuse large B cell lymphoma

The transcription factor FOXP1 is prominently expressed in mature B cells and is a potential oncogene in B cell non-Hodgkin lymphomas; however, the functions of FOXP1 in mature B cells and B cell lymphomagenesis have not yet been fully explored. In the first part of this thesis, the roles of FOXP1 in B cell biology and lymphomagenesis are studied. Our studies show that FOXP1 directly represses a set of pro-apoptotic genes and key regulators of plasma cell differentiation in primary human mature B cells. Overexpression of FOXP1 promotes survival and outgrowth of these cells by cooperating with the NF-κB pathway. Furthermore, FOXP1 downregulation is required for efficient plasma cell differentiation. We also identified the nature of the smaller FOXP1 isoform that is highly expressed in ABC-type diffuse large B cell lymphoma (DLBCL). We showed that upon overexpression in primary human B cells, this isoform regulates the same set of genes and exerts an equally strong effect on survival and plasma cell differentiation, as compared to FOXP1 full-length. DLBCL is a heterogeneous diagnostic class of lymphomas comprising molecularly distinct subtypes. Various mutations affecting the NF-κB pathway occur in ABC-DLBCL, of which MyD88 and CD79B mutations are among the most prevalent. In the second part of this thesis the prevalence of oncogenic CD79B and MYD88 mutations, and their relation to clinical, phenotypic, and molecular parameters is explored in a large panel of DLBCL patients. Our studies show specific high prevalence of these mutations in DLBCLs presenting at immune privileged sites