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Richter transformation driven by Epstein–Barr virus reactivation during therapy‐related immunosuppression in chronic lymphocytic leukaemia
The Journal of pathology, 2018-05, Vol.245 (1), p.61-73
García‐Barchino, Maria J
Sarasquete, Maria E
Panizo, Carlos
Morscio, Julie
Martinez, Antonio
Alcoceba, Miguel
Fresquet, Vicente
Gonzalez‐Farre, Blanca
Paiva, Bruno
Young, Ken H
Robles, Eloy F
Roa, Sergio
Celay, Jon
Larrayoz, Marta
Rossi, Davide
Gaidano, Gianluca
Montes‐Moreno, Santiago
Piris, Miguel A
Balanzategui, Ana
Jimenez, Cristina
Rodriguez, Idoia
Calasanz, Maria J
Larrayoz, Maria J
Segura, Victor
Garcia‐Muñoz, Ricardo
Rabasa, Maria P
Yi, Shuhua
Li, Jianyong
Zhang, Mingzhi
Xu‐Monette, Zijun Y
Puig‐Moron, Noemi
Orfao, Alberto
Böttcher, Sebastian
Hernandez‐Rivas, Jesus M
Miguel, Jesus San
Prosper, Felipe
Tousseyn, Thomas
Sagaert, Xavier
Gonzalez, Marcos
Martinez‐Climent, Jose A
2018
Volltextzugriff (PDF)
Details
Autor(en) / Beteiligte
García‐Barchino, Maria J
Sarasquete, Maria E
Panizo, Carlos
Morscio, Julie
Martinez, Antonio
Alcoceba, Miguel
Fresquet, Vicente
Gonzalez‐Farre, Blanca
Paiva, Bruno
Young, Ken H
Robles, Eloy F
Roa, Sergio
Celay, Jon
Larrayoz, Marta
Rossi, Davide
Gaidano, Gianluca
Montes‐Moreno, Santiago
Piris, Miguel A
Balanzategui, Ana
Jimenez, Cristina
Rodriguez, Idoia
Calasanz, Maria J
Larrayoz, Maria J
Segura, Victor
Garcia‐Muñoz, Ricardo
Rabasa, Maria P
Yi, Shuhua
Li, Jianyong
Zhang, Mingzhi
Xu‐Monette, Zijun Y
Puig‐Moron, Noemi
Orfao, Alberto
Böttcher, Sebastian
Hernandez‐Rivas, Jesus M
Miguel, Jesus San
Prosper, Felipe
Tousseyn, Thomas
Sagaert, Xavier
Gonzalez, Marcos
Martinez‐Climent, Jose A
Titel
Richter transformation driven by Epstein–Barr virus reactivation during therapy‐related immunosuppression in chronic lymphocytic leukaemia
Ist Teil von
The Journal of pathology, 2018-05, Vol.245 (1), p.61-73
Ort / Verlag
Chichester, UK: John Wiley & Sons, Ltd
Erscheinungsjahr
2018
Quelle
Wiley-Blackwell Journals
Beschreibungen/Notizen
The increased risk of Richter transformation (RT) in patients with chronic lymphocytic leukaemia (CLL) due to Epstein–Barr virus (EBV) reactivation during immunosuppressive therapy with fludarabine other targeted agents remains controversial. Among 31 RT cases classified as diffuse large B‐cell lymphoma (DLBCL), seven (23%) showed EBV expression. In contrast to EBV– tumours, EBV+ DLBCLs derived predominantly from IGVH‐hypermutated CLL, and they also showed CLL‐unrelated IGVH sequences more frequently. Intriguingly, despite having different cellular origins, clonally related and unrelated EBV+ DLBCLs shared a previous history of immunosuppressive chemo‐immunotherapy, a non‐germinal centre DLBCL phenotype, EBV latency programme type II or III, and very short survival. These data suggested that EBV reactivation during therapy‐related immunosuppression can transform either CLL cells or non‐tumoural B lymphocytes into EBV+ DLBCL. To investigate this hypothesis, xenogeneic transplantation of blood cells from 31 patients with CLL and monoclonal B‐cell lymphocytosis (MBL) was performed in Rag2–/– IL2γc–/– mice. Remarkably, the recipients' impaired immunosurveillance favoured the spontaneous outgrowth of EBV+ B‐cell clones from 95% of CLL and 64% of MBL patients samples, but not from healthy donors. Eventually, these cells generated monoclonal tumours (mostly CLL‐unrelated but also CLL‐related), recapitulating the principal features of EBV+ DLBCL in patients. Accordingly, clonally related and unrelated EBV+ DLBCL xenografts showed indistinguishable cellular, virological and molecular features, and synergistically responded to combined inhibition of EBV replication with ganciclovir and B‐cell receptor signalling with ibrutinib in vivo. Our study underscores the risk of RT driven by EBV in CLL patients receiving immunosuppressive therapies, and provides the scientific rationale for testing ganciclovir and ibrutinib in EBV+ DLBCL. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Sprache
Englisch
Identifikatoren
ISSN: 0022-3417
eISSN: 1096-9896
DOI: 10.1002/path.5060
Titel-ID: cdi_proquest_journals_2025089756
Format
–
Schlagworte
Activation
,
Blood cells
,
Chronic lymphocytic leukemia
,
EBV
,
Epstein-Barr virus
,
Fludarabine
,
Ganciclovir
,
Genetic transformation
,
Immunosuppression
,
Immunosuppressive agents
,
Immunosurveillance
,
Immunotherapy
,
Latency
,
Leukemia
,
Lymphocytes
,
Lymphocytes B
,
Lymphocytosis
,
Lymphoma
,
Phenotypes
,
RAG2 protein
,
Richter transformation
,
therapy‐related immunosuppression
,
Transformations
,
Transplantation
,
Tumors
,
Viruses
,
Xenografts
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