Abstract
Post-transplant lymphoproliferative disorders (PTLD) and Burkitt's lymphoma (BL) are B-cell malignancies strongly associated with Epstein-Barr virus (EBV) infection. In these lymphoproliferative disorders, EBV infection induces an increase in the expression of the anti-apoptotic protein BCL-2. Given its chemoprotective effect, BCL-2 constitutes an attractive target for new therapeutic strategies for EBV-positive B-cell malignancies. Here, we show that ABT-737, a small inhibitor of BCL-2, BCL-X(L), and BCL-w, strongly induced apoptosis invitro in EBV-positive lymphoblastoid cell lines (which is a model for PTLD), whereas BL was less sensitive. ABT-737 reduced tumor growth and increased the overall survival of mice in a xenograft model of PTLD but had no effect on BL xenograft mice. ABT-737 combined with a low dose of cyclophosphamide, a major component of the conventional CHOP chemotherapy regimen for BL patients, reduced tumor growth during treatment but failed to improve the overall survival of BL xenograft mice. By contrast, the combination of ABT-737 and rituximab, one of the main options for the treatment of PTLD, was highly efficient and induced approximately 70% remission in PTLD xenograft mice. These results suggest that the use of agents targeting BCL-2, either alone or in combination with other conventional drugs, represents a novel promising approach for post-transplant EBV-positive B lymphoproliferative disorders.
Highlights
Epstein–Barr virus (EBV), a ubiquitous B-lymphotropic herpesvirus, was the first virus directly linked to cancer in humans
We first tested the induction of apoptosis by ABT-737 in vitro on an EBV-negative cell line (BL2) and on a panel of EBV-positive cell lines, including Burkitt’s lymphoma (BL) cell lines (BL2/B95, Seraphina, and LY47) and lymphoblastoid cell lines (LCL) (RPMI8866, Remb1, and Priess), used as models of Post-transplant lymphoproliferative disorders (PTLD) (Fig. 1)
Tumor cells infected by the oncogenic EBV express latency proteins, among which LMP1 is able to increase the level of various anti-apoptotic proteins of the BCL-2 family
Summary
Epstein–Barr virus (EBV), a ubiquitous B-lymphotropic herpesvirus, was the first virus directly linked to cancer in humans. EBV has been associated with a heterogeneous group of epithelial tumors and Bcell malignancies, including Burkitt’s lymphoma (BL) and post-transplant lymphoproliferative disorders (PTLD). EBV remains latent in an episomal form, with only a small subset of viral proteins expressed, which include six nuclear antigens (EBNA) and three latent membrane proteins (LMP).
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