Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma throughout the world. B-cell lymphoma 6 (BCL6) overexpression is frequently observed in DLBCL. Several recent studies have supported that BCL6 is a critical pathogenic oncoprotein in DLBCL. BCL6 represses various downstream genes, including ATR, TP53 and CDKN1A, thereby impairing DNA repair leading to derangement of cellular proliferation. Most importantly, a specific small molecule inhibitor targeting BCL6 successfully suppressed growth of BCL6-dependent DLBCL cell lines and primary human DLBCL cells, further suggesting that BCL6 plays an important pathogenetic role. Arsenic trioxide (As2O3) has been reported to target various oncogenic proteins, including PML-RARA in acute promyelocytic leukemia, cyclin D1 in mantle cell lymphoma, NPMc+ in acute myeloid leukemia and NPM-ALK in anaplastic large cell lymphoma, for degradation through ubiquitin-proteasome pathway. In this study, we investigated the effects of As2O3 on BCL6 in DLBCL.
As2O3 was found to inhibit cell proliferation and induce cell death via apoptosis in DLBCL cells. More interestingly, BCL6-dependent DLBCL cells were found to show higher sensitivity towards As2O3-induced cytotoxicity. BCL6 was found to be degraded by As2O3 at posttranslational level through the ubiquitin-proteasome pathway. Such degradation led to an upregulation of several downstream targets of BCL6, including PRDM1, CD44 and CD69. Moreover, As2O3 synergized with cisplatin to inhibit cell proliferation and enhance apoptosis in BCL6-dependent DLBCL cell lines. Concomitant treatment with As2O3 and cisplatin further enhanced the phosphorylation of Chk1 and γH2AX in these cells.
In conclusion, our data suggest that As2O3 is a potential therapeutic agent for the treatment of BCL6-dependent DLBCL. On top of that, new combination therapies can be developed to expand the therapeutic spectrum of As2O3 to other neoplasms.
Citation Format: Lok Man Yue, David Hau Wing Chau, Wenying Piao, (Eric) Wai Choi Tse, Yok Lam Kwong. Arsenic trioxide targets BCL6 oncoprotein for degradation in BCL6-dependent diffuse large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2166. doi:10.1158/1538-7445.AM2017-2166