Menter Thomas, Dickenmann Michael, Juskevicius Darius, Steiger Juerg, Dirnhofer Stephan, Tzankov Alexandar
Institute of Pathology, University Hospital Basel, Basel, Switzerland.
Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.
Hematol Oncol. 2017 Jun;35(2):187-197. doi: 10.1002/hon.2280. Epub 2016 Jan 22.
Post-transplant lymphoproliferative disorders (PTLD) are a major problem in transplant medicine. So far, the insights into pathogenesis and potentially druggable pathways in PTLD remain scarce. We investigated a cohort of PTLD patients, consisting of both polymorphic (n = 3) and monomorphic (n = 19) B-cell lymphoproliferations. Several signalling pathways, cell of origin of PTLD and their relation to viruses were analysed by immunohistochemistry and in situ hybridization. Most PTLD were of activated B-cell origin. Two-thirds of cases showed an Epstein-Barr virus (EBV) infection of the neoplastic cells. NF-κB signalling components were present in the majority of cases, except for EBV-infected cases with latency type III lacking CD19 and upstream B-cell signalling constituents. Proteins involved in B-cell receptor signalling like Bruton tyrosine kinase were only present in a minority of cases. Phosphoinositide 3-kinase (PI3K) was expressed in 94% of cases and the druggable PI3K class 1 catalytic subunit p110 in 76%, while proteins of other signalling transduction pathways were expressed only in single cases. Unsupervised cluster analysis revealed three distinct subgroups: (i) related to EBV infection, mainly latency type III and mostly lacking CD19, upstream B-cell signalling and NF-κB constituents; (ii) mostly related to EBV infection with expression of the alternative NF-κB pathway compound RelB, CD10, and FOXP1 or MUM1; and finally, (iii) mostly unrelated to virus infection with expression of the classic NF-κB pathway compound p65. EBV and NF-κB are important drivers in PTLD in contrast to B-cell receptor signalling. The main signal transduction pathway is related to PI3K. This links PTLD to other subgroups of EBV-related lymphomas, highlighting also new potential treatment approaches. Copyright © 2016 John Wiley & Sons, Ltd.
移植后淋巴组织增生性疾病（PTLD）是移植医学中的一个主要问题。到目前为止，对PTLD发病机制和潜在可药物治疗途径的认识仍然很少。我们调查了一组PTLD患者，包括多形性（n = 3）和单形性（n = 19）B细胞淋巴增生。通过免疫组织化学和原位杂交分析了几种信号通路、PTLD的细胞起源及其与病毒的关系。大多数PTLD起源于活化B细胞。三分之二的病例显示肿瘤细胞有EB病毒（EBV）感染。除了缺乏CD19和上游B细胞信号成分的III型潜伏性EBV感染病例外，大多数病例中存在NF-κB信号成分。参与B细胞受体信号传导的蛋白质如布鲁顿酪氨酸激酶仅在少数病例中存在。94%的病例中表达磷酸肌醇3激酶（PI3K），76%的病例中表达可药物作用的PI3K 1类催化亚基p110，而其他信号转导途径的蛋白质仅在个别病例中表达。无监督聚类分析揭示了三个不同的亚组：（i）与EBV感染相关，主要是III型潜伏性感染，大多缺乏CD19、上游B细胞信号和NF-κB成分；（ii）大多与EBV感染相关，表达替代NF-κB途径化合物RelB、CD10和FOXP1或MUM1；最后，（iii）大多与病毒感染无关，表达经典NF-κB途径化合物p65。与B细胞受体信号传导相比，EBV和NF-κB是PTLD的重要驱动因素。主要信号转导途径与PI3K有关。这将PTLD与EBV相关淋巴瘤的其他亚组联系起来，也突出了新的潜在治疗方法。版权所有© 2016约翰威立父子有限公司。
