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Non-Hodgkin Lymphoma
Targeting BCL2 with venetoclax is a promis- ing therapeutic strategy for “double-protein- expression” lymphoma with MYC and BCL2 rearrangements
Ferrata Storti Foundation
Haematologica 2019 Volume 104(7):1417-1427
Akiko Uchida,1* Yasushi Isobe,1* Junko Asano,1 Yu Uemura,1 Masahiro Hoshikawa,2 Masayuki Takagi2 and Ikuo Miura1
1Division of Hematology and Oncology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa and 2Department of Pathology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan
*AU and YI contributed equally to this work.
ABSTRACT
The so-called “double-hit” and “double-protein-expression” lym- phoma with MYC and BCL2 rearrangements is a rare, mature B-cell neoplasm characterized by a germinal center B-cell phenotype, abun- dant protein expression of MYC and BCL2, rapid disease progression, and a poor prognosis. In this study, we showed the potential benefit of the BCL2 inhibitor venetoclax in the treatment of this disease. Immunohistochemical studies of the lymphoma tissues confirmed that overexpression of MYC and BCL2 was observed more frequently in this subtype than in other germinal center B-cell-like diffuse large B-cell lym- phomas. In contrast, another pro-survival protein MCL1 was less expressed in this subtype, even when compared with its expression in the non-“dou- ble-hit” and “double-protein-expression” type. Furthermore, in vitro studies using two “double-hit” and “double-protein-expression” lymphoma- derived cell lines, Karpas231 and OCI-Ly8, clearly showed that a low con- centration of venetoclax, but not the MCL1 inhibitor S63845, was sufficient to induce apoptosis in the two lines, compared with in other germinal cen- ter B-cell-derived cell lines, BJAB and SU-DHL10. These results indicate that the survival of this type of lymphoma depends predominantly on BCL2 rather than on MCL1. Unexpectedly, we found that venetoclax not only disrupts the interaction between BCL2 and the pro-apoptotic protein BIM, but also leads to dephosphorylation of BCL2 and further downregulates MCL1 protein expression, probably through modulation of the protein phosphatase 2A B56a activity in Karpas231 and OCI-Ly8. Indeed, a low concentration of venetoclax induced substantial apoptosis in the primary lymphoma cells, regardless of high protein expression of MCL1 associated with venetoclax resistance. Venetoclax clearly triggers the signal transduc- tion related to BCL2 and MCL1 in “double-hit” and “double-protein-expres- sion” lymphoma cells.
Introduction
Aggressive mature B-cell lymphomas harboring concurrent translocations of 8q24/MYC mainly with 18q21/BCL2 are called “double-hit lymphomas (DHL)” now referred to as “high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (DH-HGBL)” according to the current World Health Organization (WHO) classification of lymphoid neoplasms.1 The concurrent translocations of 8q24/MYC and 18q21/BCL2 usually lead to overexpression of both proteins, and DH-HGBL clinically forms a specific group among “double-protein-expression lym- phomas (DPL)”.1-3 The most common histological type of DH-HGBL is diffuse large B-cell lymphoma (DLBCL), which has heterogeneous clinicopathological,
Correspondence:
YASUSHI ISOBE
yisobe@marianna-u.ac.jp
Received: August 21, 2018. Accepted: November 23, 2018. Pre-published: December 6, 2018.
doi:10.3324/haematol.2018.204958
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/7/1417
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