In vivo intratumoral Epstein-Barr virus replication is associated with XBP1 activation and early-onset post-transplant lymphoproliferative disorders with prognostic implications.
Post-transplant lymphoproliferative disorders are life-threatening complications following hematopoietic or solid organ transplantation. They represent a spectrum of mostly EBV-driven lymphoplasmacytic proliferations. While the oncogenic effect of EBV is related to latent infection, lytic infection also has a role in lymphomagenesis. In vitro, EBV replication is linked to plasma cell differentiation and XBP1 activation, although this phenomenon has never been addressed in vivo. We analyzed for the first time latent and lytic intratumoral EBV infection in a series of 35 adult patients with a diagnosis of post-transplant lymphoproliferative disorder (26M/9F, median age 54 years). A complete EBV study was performed including the analysis of the latent EBER, latent membrane protein-11, and EBV nuclear antigens as well as the immediate-early BZLF1/ZEBRA and early BMRF1/EADE31 lytic genes. XBP1 activation was assessed by nuclear protein expression. EBV infection was observed in 28 (80%) cases being latency II and III the most frequently observed 22 (79%). Intratumoral EBV replication was detected in 17 (60%) cases. Among these, XBP1 activation was observed in 11/12 evaluable cases associated with strong cytoplasmic immunoglobulin expression consistent with plasma cell differentiation. Intriguingly, the combination of latency III infection and EBV replication identified a high-risk subgroup of patients with significantly shorter survival (overall survival at 1 year 18% vs 48%) and early-onset (median of 7 vs 26 months) post-transplant lymphoproliferative disorder. Moreover, these patients appear to be more heavily immunosuppressed, so they exhibit lower rates of rejection and graft vs host disease but higher rates of cytomegalovirus reactivation. In conclusion, EBV replication is associated with plasma cell differentiation and XBP1 activation with prognostic implications. Both latency III and lytic EBV infection are related to aggressive and early-onset post-transplant lymphoproliferative disorder. These results suggest that immunohistochemical study of latent and lytic EBV genes in the clinical practice may help to select higher-risk patients to new therapies including antiviral treatments.
Department of Pathology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
Blanca
B
Gonzalez-Farre
Hematology Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain.
Jordina
J
Rovira
Department of Pathology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
Daniel
D
Martinez
Department of Pathology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
Alexandra
A
Valera
Department of Pathology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
Adriana
A
Garcia-Herrera
Department of Microbiology, Barcelona Centre for International Health Research (CRESIB), Hospital Clínic, University of Barcelona, Barcelona, Spain.
Maria Angeles
MA
Marcos
Experimental Therapy in Lymphpoid Malignancies Group, Institut d'Investigacions Biomediques Agusti Pi i Sunyer (IDIBAPS), University of Barcelona, Centre Esther Koplowitz, Barcelona, Spain.
Carla
C
Sole
Experimental Therapy in Lymphpoid Malignancies Group, Institut d'Investigacions Biomediques Agusti Pi i Sunyer (IDIBAPS), University of Barcelona, Centre Esther Koplowitz, Barcelona, Spain.
Gael
G
Roue
1] Department of Pathology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain [2] Experimental Therapy in Lymphpoid Malignancies Group, Institut d'Investigacions Biomediques Agusti Pi i Sunyer (IDIBAPS), University of Barcelona, Centre Esther Koplowitz, Barcelona, Spain.
Dolors
D
Colomer
Department of Pathology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
Elena
E
Gonzalvo
1] Department of Pathology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain [2] Department of Pathology, Hospital Nostra Senyora de Meritxell, Escaldes-Engordany, Principat d'Andorra, Spain.
Imma
I
Ribera-Cortada
Department of Pathology, Hospital San Juan de Dios, San José, Costa Rica.
Monica
M
Araya
Department of Pathology, Hospital del Mar, Institut Municipal d'Investigacions Mèdiques (IMIM), Autonomous University of Barcelona, Barcelona, Spain.
Josep
J
Lloreta
Department of Pathology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
Luis
L
Colomo
Department of Pathology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
Elias
0000000198509793
E
Campo
Hematology Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain.
Armando
A
Lopez-Guillermo
Department of Pathology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
Antonio
A
Martinez
D000328:Adult; D000368:Aged; D015153:Blotting, Western; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020031:Epstein-Barr Virus Infections / Q000378:metabolism / Q000401:mortality / Q000821:virology*; D005260:Female; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D016867:Immunocompromised Host / Q000276:immunology; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008232:Lymphoproliferative Disorders / Q000276:immunology* / Q000401:mortality / Q000821:virology*; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation / Q000009:adverse effects; D010950:Plasma Cells / Q000821:virology; D011379:Prognosis; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D014779:Virus Replication; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human