Molecular pathogenesis of nodular lymphocyte predominant Hodgkin lymphoma and related neoplasias

结节性淋巴细胞为主的霍奇金淋巴瘤及相关肿瘤的分子发病机制

• 批准号: 390340829
• 负责人: Professorin Dr. Sylvia Hartmann
• 金额: --
• 依托单位: Dr. Senckenbergisches Institut für Pathologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/390340829?language=en
• 关键词: Molecular; pathogenesis; nodular; lymphocyte; predominant

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.

结节淋巴细胞占优势的霍奇金淋巴瘤(NLPHL)与经典型霍奇金淋巴瘤(CHL)有许多不同之处，包括保留B细胞表型、男性占优势和临床表现懒惰。在目前的资助期间，我们通过对NLPHL-DLBCL复合性淋巴瘤的弥漫性大细胞淋巴瘤(DLBCL)成分的全基因组测序，在NLPHL中发现了三个新的重复突变基因SGK1、DUSP2和JunB。此外，对从NLPHL转化而来的更大系列的DLBCL进行了基因表达谱研究，发现在几例病例的肿瘤细胞中，PD-L1的表达和MYC的下调具有显著的宿主抗淋巴瘤反应。富含T细胞/组织细胞的大B细胞淋巴瘤(THRLBCL)和THRLBCL样NLPHL通常难以区分。我们在这里研究了新生血管的模式，这进一步支持了两种淋巴瘤类型之间的强烈关系。另一个诊断挑战是鉴别进行性转化的生发中心(PTGC)和NLPHL的早期淋巴转移。我们描述了五种典型的PTGC类型，这有助于病理学家区分非肿瘤性PTGC和早期NLPHL。考虑到小男孩可能会受到NLPHL的影响，NLPHL通常是IGD阳性的，我们有一个假设，即儿童NLPHL可能是由一种在儿童中经常观察到的传染病引发的。从原代LP细胞的B细胞受体序列中提取的重组Fab片段被用来对抗细菌裂解物，事实上，有几个案例显示出对卡他莫拉氏菌裂解物的反应。在新的资助时期，我们的目标是寻找更多与NLPHL发病相关的突变基因。因此，我们计划对从原代NLPHL获得的3000个显微解剖的LP细胞的整个外显子组进行测序。此外，我们还希望从基因突变的角度进一步阐明NLPHL与THRLBCL的关系。在NLPHL中频繁突变的候选基因将应用定制的浓缩方法在THRLBCL病例的子集中进行突变筛查。此外，我们还旨在阐明持续免疫反应和T细胞库在NLPHL肿瘤维持中的作用。为此，将对卡他支原体相关性NLPHL患者LP细胞周围的T细胞进行显微解剖，并对T细胞受体γ基因进行聚合酶链式反应(PCR)扩增和测序。如果我们的假设是正确的，即NLPHL肿瘤需要持续的T细胞反应，我们有望发现寡克隆T细胞群。此外，目前还不清楚为什么NLPHL可以表现出不同的生长模式，并具有预后意义。将测试特定的组织病理生长模式的发生是否与某些人类白细胞抗原亚型有关。最后，我们计划研究在NLPHL中发现的新突变基因的功能作用。