Development of a novel cell line‐derived xenograft model of primary herpesvirus 8‐unrelated effusion large B‐cell lymphoma and antitumor activity of birabresib in vitro and in vivo

Abstract

Background Primary human herpesvirus 8 (HHV8)‐unrelated effusion large B‐cell lymphoma is a clinical disease entity distinct from HHV8‐positive primary effusion lymphoma (PEL). However, the lack of experimental HHV8‐unrelated effusion large B‐cell lymphoma models continues to hinder the pathophysiologic and therapeutic investigations of this disorder. Methods The lymphoma cells were obtained from the pleural effusion of a patient with primary HHV8‐unrelated effusion large B‐cell lymphoma and cultured in vitro. Results We established a novel HHV8‐unrelated effusion large B‐cell lymphoma cell line, designated Pell‐1, carrying a c‐MYC rearrangement with features distinct from those of HHV8‐positive PEL. Moreover, we developed an HHV8‐unrelated effusion large B‐cell lymphoma cell line‐derived xenograft model. Pell‐1 cells induced profuse lymphomatous ascites and subsequently formed intra‐abdominal tumors after intraperitoneal implantation into irradiated nonobese diabetic/severe combined immunodeficient mice. Thus, this xenograft mouse model mimicked the clinical phenomena observed in patients and recapitulated the sequential stages of aggressive HHV8‐unrelated effusion large B‐cell lymphoma. The bromodomain and extraterminal domain (BET) inhibitors JQ1 and birabresib (MK‐8628/OTX015) reduced the proliferation of Pell‐1 cells in vitro through the induction of cell cycle arrest and apoptosis. The antitumor effect of BET inhibition was also demonstrated in vivo, as birabresib significantly reduced ascites and suppressed tumor progression without apparent adverse effects in the xenografted mice. Conclusion These preclinical findings suggest the therapeutic potential of targeting c‐MYC through BET inhibition in HHV8‐unrelated effusion large B‐cell lymphoma.

Targeting VEGF with bevacizumab inhibits malignant effusion formation of primary human herpesvirus 8‐unrelated effusion large B‐cell lymphoma in vivo

“…The second is whether the antitumour effect of bevacizumab can be improved by combining with cytotoxic agents or with agents targeting other molecules such as c-MYC. 17 Our study has some limitations. First, we cannot explain why mice injected with STR-428 or OGU1 cells developed neither noticeable ascites nor peritoneal tumours, even though these can grow in culture medium with lower concentrations of FBS than that used in the culture of Pell-1 and Pell-2 cells.…”

“…and Pell-1, all of which were derived from Japanese patients, have been characterized in detail. 17 Cell culture systems provide limited information because of the different microenvironment from that in vivo. In our study, Pell-1 and Pell-2 cells produced effusion lymphomas with prominent ascites when injected into the peritoneal cavity of irradiated NOD/ SCID mice.…”

“…The detailed characteristics of Pell-1 are described elsewhere. 17 In the current study, we established a new cell line, Pell-2, from the pleural effusion of an HIV-uninfected Japanese patient with HHV8-unrelated ELBCL. Derivation of the Pell-2 cell line was authenticated using short tandem repeat DNA profiling as previously described.…”

“…We have previously established an HHV8‐unrelated ELBCL cell line, designated Pell‐1 and generated the first cell line‐derived xenograft (CDX) model that captures the clinical phenomena observed in patients and recapitulates the successive stages of the disease progression 17 . We have successfully generated a new HHV8‐unrelated ELBCL cell line, Pell‐2 and its CDX model.…”

“…We have previously established an HHV8‐unrelated ELBCL cell line, designated Pell‐1 and generated the first cell line‐derived xenograft (CDX) model that captures the clinical phenomena observed in patients and recapitulates the successive stages of the disease progression. 17 We have successfully generated a new HHV8‐unrelated ELBCL cell line, Pell‐2 and its CDX model. In this study, using these novel CDX models, we examined the antitumour effects of the anti‐VEGF monoclonal antibody bevacizumab on HHV8‐unrelated ELBCL cells growing in effusions developed in the body cavity of mice, and we describe here the rationale for VEGF‐targeted treatment modalities for this disease.…”