Epstein Barr virus-positive B-cell lymphoma is highly vulnerable to MDM2 inhibitors in vivo

Epstein-Barr virus (EBV)-positive B-cell lymphomas are common in immunocompromised patients and remain an unmet medical need. Here we report that MDM2 inhibitors (MDM2i) navtemadlin and idasanutlin have potent in vivo activity in EBV+ B-cell lymphoma established in immunocompromised mice. Tumor regression was observed in all 5 EBV+ xenograft-associated B-cell lymphomas treated with navtemadlin or idasanutlin. Molecular characterization showed that treatment with MDM2i resulted in activation of p53 pathways and downregulation of cell cycle effectors in human lymphoma cell lines that either were EBV+ or had undetectable expression of BCL6, a transcriptional inhibitor of the TP53 gene. Moreover, treatment with navtemadlin resulted in tumor regression and prevented systemic dissemination of EBV+ lymphoma derived from 2 juvenile patients with posttransplant lymphoproliferative diseases, including one whose tumor was resistant to virus-specific T-cell therapy. These results provide proof-of-concept for targeted therapy of EBV+ lymphoma with MDM2i and the feasibility of using EBV infection or loss of BCL6 expression to identify responders to MDM2i.

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Virally Induced Cellular MicroRNA miR-155 Plays a Key Role in B-Cell Immortalization by Epstein-Barr Virus

Journal of Virology ◽

10.1128/jvi.01248-10 ◽

2010 ◽

Vol 84 (22) ◽

pp. 11670-11678 ◽

Cited By ~ 129

Author(s):

Sarah D. Linnstaedt ◽

Eva Gottwein ◽

Rebecca L. Skalsky ◽

Micah A. Luftig ◽

Bryan R. Cullen

Keyword(s):

B Cell ◽

Cell Lines ◽

Epstein Barr Virus ◽

B Cell Lymphoma ◽

Selective Inhibition ◽

B Cell Lymphomas ◽

Cell Infection ◽

Barr Virus ◽

Epstein Barr

ABSTRACT Infection of resting primary human B cells by Epstein-Barr virus (EBV) results in their transformation into indefinitely proliferating lymphoblastoid cell lines (LCLs). LCL formation serves as a model for lymphomagenesis, and LCLs are phenotypically similar to EBV-positive diffuse large B-cell lymphomas (DLBCLs), which represent a common AIDS-associated malignancy. B-cell infection by EBV induces the expression of several cellular microRNAs (miRNAs), most notably miR-155, which is overexpressed in many tumors and can induce B-cell lymphomas when overexpressed in animals. Here, we demonstrate that miR-155 is the most highly expressed miRNA in LCLs and that the selective inhibition of miR-155 function specifically inhibits the growth of both LCLs and the DLBCL cell line IBL-1. Cells lacking miR-155 are inefficient in progressing through S phase and spontaneously undergo apoptosis. In contrast, three other B-cell lymphoma lines, including two EBV-positive Burkitt's lymphoma cell lines, grew normally in the absence of miR-155 function. These data identify the induction of cellular miR-155 expression by EBV as critical for the growth of both laboratory-generated LCLs and naturally occurring DLBCLs and suggest that targeted inhibition of miR-155 function could represent a novel approach to the treatment of DLBCL in vivo.

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Transformation of Small B-Cell Lymphoma Into Large Cell CD30+, CD4+, Epstein-Barr Virus–Negative Lymphoma

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2013-0089-cr ◽

2014 ◽

Vol 138 (8) ◽

pp. 1101-1105 ◽

Cited By ~ 1

Author(s):

Aaron C. Shaver ◽

Ly Ma ◽

Cindy Vnencak-Jones ◽

Roland S. Schwarting ◽

Kristina J. Fasig ◽

...

Keyword(s):

B Cell ◽

Epstein Barr Virus ◽

Cell Lymphoma ◽

Relevant Literature ◽

B Cell Lymphoma ◽

Low Grade ◽

B Cell Lymphomas ◽

Barr Virus ◽

Wide Range ◽

Epstein Barr

We report here 2 separate cases in which patients with known low-grade B-cell lymphomas presented with transformed lesions that were CD30+, CD4+, Epstein-Barr virus negative, and negative or focally weak for a wide range of B-cell, T-cell, and histiocytic/dendritic cell markers. In each case the transformed lymphoma possessed an identical pattern of immunoglobulin heavy chain and/or BCL2 rearrangement to the corresponding original low-grade B-cell lymphoma, confirming their identity as transformed B-cell lymphoma. A review of the relevant literature reveals that, to our knowledge, no transformed B-cell lymphomas with this immunophenotype have been previously reported, which creates the opportunity for potential errors of diagnosis. These cases highlight the importance of correlation with the patient's history and with molecular genetic results in rendering an accurate diagnosis.

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Imatinib mesylate reduces rituximab-induced tumor-growth inhibition in vivo on Epstein???Barr virus-associated human B-cell lymphoma

Anti-Cancer Drugs ◽

10.1097/cad.0b013e3281e444cb ◽

2007 ◽

Vol 18 (9) ◽

pp. 1029-1037 ◽

Cited By ~ 2

Author(s):

Fariba N??mati ◽

Claire Mathiot ◽

Isabelle Grandjean ◽

Olivier Lantz ◽

Vincent Bordier ◽

...

Keyword(s):

Growth Inhibition ◽

B Cell ◽

Epstein Barr Virus ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Tumor Growth Inhibition ◽

Barr Virus ◽

Epstein Barr ◽

Human B Cell

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Induction of Lytic Epstein-Barr Virus (EBV) Infection by Synergistic Action of Rituximab and Dexamethasone Renders EBV-Positive Lymphoma Cells More Susceptible to Ganciclovir Cytotoxicity In Vitro and In Vivo

Journal of Virology ◽

10.1128/jvi.79.9.5875-5879.2005 ◽

2005 ◽

Vol 79 (9) ◽

pp. 5875-5879 ◽

Cited By ~ 27

Author(s):

Masanori Daibata ◽

Kentaro Bandobashi ◽

Masayuki Kuroda ◽

Shosuke Imai ◽

Isao Miyoshi ◽

...

Keyword(s):

B Cell ◽

Epstein Barr Virus ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Lymphoma Cells ◽

Barr Virus ◽

Ebv Infection ◽

Epstein Barr

ABSTRACT The purposeful induction of the lytic form of Epstein-Barr virus (EBV) infection combined with ganciclovir (GCV) treatment has been advocated as a novel strategy for EBV-positive B-cell lymphoma. We demonstrated that rituximab had a synergistic effect with dexamethasone on induction of the lytic EBV infection in CD20-positive lymphoma cells. Addition of GCV to the dexamethasone/rituximab-treated cells was more effective than dexamethasone/rituximab alone in killing EBV-positive lymphoma cells in vitro and in lymphoma-bearing nude mice but not in EBV-negative cells. These data suggest that induction of the lytic EBV infection with dexamethasone/rituximab in combination with GCV could be a potential virally targeted therapy for EBV-associated B-cell lymphoma.

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