Molecular pathogenesis of nodular lymphocyte predominant Hodgkin lymphoma and related neoplasias

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Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) displays a variety of differences to classical Hodgkin lymphoma (cHL), which consist of a preserved B cell phenotype, a strong male predominance and an indolent clinical behavior. In the present funding period we were able to identify three novel recurrently mutated genes, SGK1, DUSP2 and JUNB in NLPHL, by whole genome sequencing of the diffuse large cell lymphoma (DLBCL) component of NLPHL-DLBCL composite lymphomas. Furthermore, a larger series of DLBCL transformed from NLPHL was investigated by gene expression profiling which revealed a prominent host anti-lymphoma reaction with PD-L1 expression and a downregulation of MYC in the tumor cells of several cases. T cell/histiocyte rich large B cell lymphoma (THRLBCL) and THRLBCL-like NLPHL are often difficult to delineate. We studied here the patterns of neovascularization which furthermore support the strong relationship between both lymphoma types. Another diagnostic challenge is the differentiation between progressively transformed germinal centers (PTGC) and early involvement of the lymph node by NLPHL. We described five typical patterns of PTGC, which facilitate pathologists to differentiate between non-neoplastic PTGC and early NLPHL. Given that young boys can be affected by NLPHL, which is often IgD-positive, we had the hypothesis that pediatric NLPHL could be triggered by an infectious disease which is frequently observed in children. Recombinant Fab fragments derived from the B cell receptor sequences of primary LP cells were tested against bacterial lysates, and indeed, several cases showed reactivity against lysates of Moraxella catarrhalis.In the new funding period, we aim to identify further mutated genes which contribute to the pathogenesis of NLPHL. Therefore we plan to sequence the whole exome from 3000 microdissected LP cells obtained from primary NLPHL without transformation. Additionally, we want to further elucidate the relationship of NLPHL and THRLBCL based on mutated genes. Candidate genes, which are frequently mutated in NLPHL will be screened for mutations in a subset of THRLBCL cases applying a custom made enrichment approach. Moreover, we also aim to clarify the role of an ongoing immune response and the T cell repertoire in the maintenance of the NLPHL tumor. For this reason, T cells rosetting around LP cells of M. catarrhalis-associated NLPHL cases, will be microdissected and the T cell receptor gamma genes will be PCR amplified and sequenced. If our hypothesis is correct that the NLPHL tumor needs an ongoing T cell response, we would expect to find oligoclonal T cell populations. Furthermore, it is unclear, why NLPHL can show different growth patterns with prognostic implications. It will be tested if the occurrence of particular histopathologic growth patterns is associated with certain HLA subtypes. Last, we plan to study the functional role of the novel mutated genes that could be identified in NLPHL.