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Comprehensive phenotypic characterization of PTLD reveals potential reliance on EBV or NF-κB signalling instead of B-cell receptor signalling.
Journal article

Comprehensive phenotypic characterization of PTLD reveals potential reliance on EBV or NF-κB signalling instead of B-cell receptor signalling.

  • Menter T Institute of Pathology, University Hospital Basel, Basel, Switzerland.
  • Dickenmann M Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.
  • Juskevicius D Institute of Pathology, University Hospital Basel, Basel, Switzerland.
  • Steiger J Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.
  • Dirnhofer S Institute of Pathology, University Hospital Basel, Basel, Switzerland.
  • Tzankov A Institute of Pathology, University Hospital Basel, Basel, Switzerland.
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  • 2016-01-23
Published in:
  • Hematological oncology. - 2017
B-cell receptor signalling
DLBCL
EBV
NF-κB
PI3K
PTLD
Adolescent
Adult
Child
Cluster Analysis
Epstein-Barr Virus Infections
Female
Humans
Lymphoproliferative Disorders
Male
Middle Aged
NF-kappa B
Organ Transplantation
Phenotype
Receptors, Antigen, B-Cell
Signal Transduction
T-Lymphocytes, Regulatory
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/93886
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