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.

Large B-cell lymphomas that grow exclusively in body cavity effusions without identifiable tumour masses are universally associated with human herpesvirus 8 (HHV8), also called Kaposi sarcomaassociated herpesvirus, and this lymphoma entity is defined as primary effusion lymphoma (PEL) according to the 2017 World Health Organization classification. 1 PEL often appears with Epstein-Barr virus (EBV), especially in the setting of human immunodeficiency virus (HIV) infection. 1 PEL has a characteristic phenotype in that it lacks pan-B-cell markers such as CD19 and CD20 but expresses plasma cell markers such as CD138. [1][2][3] Primary HHV8-unrelated effusion lymphoma, hereinafter referred to as HHV8-unrelated effusion large B-cell lymphoma