title: Comprehensive phenotypic characterization of PTLD reveals potential reliance on EBV or NF-κB signalling instead of B-cell receptor signalling.
abstract: 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.
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Menter
authors.affiliation: Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Dickenmann
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Darius
authors.initials: D
authors.lastname: Juskevicius
authors.affiliation: Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.
authors.forename: Juerg
authors.initials: J
authors.lastname: Steiger
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Dirnhofer
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Alexandar
authors.initials: A
authors.lastname: Tzankov
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D016000:Cluster Analysis; D020031:Epstein-Barr Virus Infections / Q000150:complications*; D005260:Female; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000502:physiology*; D016377:Organ Transplantation / Q000009:adverse effects*; D010641:Phenotype; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D016328:NF-kappa B; D011947:Receptors, Antigen, B-Cell
keywords: B-cell receptor signalling; DLBCL; EBV; NF-κB; PI3K; PTLD