TY - JOUR
T1 - Richter transformation driven by Epstein–Barr virus reactivation during therapy-related immunosuppression in chronic lymphocytic leukaemia
AU - García-Barchino, Maria J.
AU - Sarasquete, Maria E.
AU - Panizo, Carlos
AU - Morscio, Julie
AU - Martinez, Antonio
AU - Alcoceba, Miguel
AU - Fresquet, Vicente
AU - Gonzalez-Farre, Blanca
AU - Paiva, Bruno
AU - Young, Ken H.
AU - Robles, Eloy F.
AU - Roa, Sergio
AU - Celay, Jon
AU - Larrayoz, Marta
AU - Rossi, Davide
AU - Gaidano, Gianluca
AU - Montes-Moreno, Santiago
AU - Piris, Miguel A.
AU - Balanzategui, Ana
AU - Jimenez, Cristina
AU - Rodriguez, Idoia
AU - Calasanz, Maria J.
AU - Larrayoz, Maria J.
AU - Segura, Victor
AU - Garcia-Muñoz, Ricardo
AU - Rabasa, Maria P.
AU - Yi, Shuhua
AU - Li, Jianyong
AU - Zhang, Mingzhi
AU - Xu-Monette, Zijun Y.
AU - Puig-Moron, Noemi
AU - Orfao, Alberto
AU - Böttcher, Sebastian
AU - Hernandez-Rivas, Jesus M.
AU - Miguel, Jesus San
AU - Prosper, Felipe
AU - Tousseyn, Thomas
AU - Sagaert, Xavier
AU - Gonzalez, Marcos
AU - Martinez-Climent, Jose A.
N1 - Publisher Copyright:
Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
PY - 2018/5
Y1 - 2018/5
N2 - 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.
AB - 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.
KW - EBV
KW - Richter transformation
KW - therapy-related immunosuppression
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U2 - 10.1002/path.5060
DO - 10.1002/path.5060
M3 - Article
C2 - 29464716
AN - SCOPUS:85044544949
SN - 0022-3417
VL - 245
SP - 61
EP - 73
JO - Journal of Pathology
JF - Journal of Pathology
IS - 1
ER -