title: Early gene expression changes by Epstein-Barr virus infection of B-cells indicate CDKs and survivin as therapeutic targets for post-transplant lymphoproliferative diseases.
abstract: Lymphoproliferative diseases (LPDs) associated with Epstein-Barr virus (EBV) infection cause significant morbidity and mortality in bone marrow and solid organ transplant recipients. To gain insight into LPD pathogenesis and to identify potential effective therapeutic approaches, we investigated early molecular events leading to B-cell transformation by gene expression profiling of EBV-infected B-cells from tonsils by Affymetrix microarray 72 hr postinfection when the B-cells hyperproliferation phase starts. Cell cycle and apoptosis were the most significantly affected pathways and enriched gene sets. In particular, we found significantly increased expression of cyclin-dependent kinase (CDK)1 and CCNB1 (cyclin B1) and of one of their downstream targets BIRC5 (survivin). Importantly, the strong upregulation of the antiapoptotic protein survivin was confirmed in lymphoblastoid cell lines (LCLs) and 71% of EBV-positive post-transplant EBV-LPD lesions scored positive for survivin. The validity of early transforming events for the identification of therapeutic targets for EBV-LPD was confirmed by the marked antiproliferative effect of the CDK inhibitor flavopiridol on LCLs and by the strong induction of apoptosis by survivin inhibition with YM155 or terameprocol. Our results suggest that targeting of CDKs and/or survivin in post-transplant EBV-LPD by specific inhibitors might be an important approach to control and eliminate EBV-transformed B-cells that should be further considered.
authors: Experimental Infectious Diseases and Cancer Research, Division of Infectious Diseases and Hospital Epidemiology, University Children's Hospital of Zurich, Zurich, Switzerland; Children's Research Center, University Children's Hospital of Zurich, Zurich, Switzerland.
authors: Michele
authors: M
authors: Bernasconi
authors: Seigo
authors: S
authors: Ueda
authors: Patricia
authors: P
authors: Krukowski
authors: Beat C
authors: BC
authors: Bornhauser
authors: Kristin
authors: K
authors: Ladell
authors: Marcus
authors: M
authors: Dorner
authors: Juerg A
authors: JA
authors: Sigrist
authors: Cristina
authors: C
authors: Campidelli
authors: Roberta
authors: R
authors: Aslandogmus
authors: Davide
authors: D
authors: Alessi
authors: Christoph
authors: C
authors: Berger
authors: Stefano A
authors: SA
authors: Pileri
authors: Roberto F
authors: RF
authors: Speck
authors: David
authors: D
authors: Nadal
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism* / Q000821:virology*; D016203:CDC2 Protein Kinase / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D020031:Epstein-Barr Virus Infections / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D015870:Gene Expression; D004854:Herpesvirus 4, Human; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000821:virology; D008232:Lymphoproliferative Disorders / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D016377:Organ Transplantation / Q000009:adverse effects*; D000077022:Survivin; D014170:Transformation, Genetic; D015854:Up-Regulation
chemical_list: C107489:BIRC5 protein, human; C534699:CCNB1 protein, human; D056744:Cyclin B1; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; D016203:CDC2 Protein Kinase
keywords: Epstein-Barr virus (EBV); post-transplant lymphoproliferative disorder (PTLD); survivin