Division of Hematology and Oncology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa.
Division of Hematology and Oncology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa
Haematologica. 2019 Jul;104(7):1417-1421. doi: 10.3324/haematol.2018.204958. Epub 2018 Dec 6.
The so-called "double-hit" and "double-protein-expression" lymphoma with and rearrangements is a rare, mature B-cell neoplasm characterized by a germinal center B-cell phenotype, abundant 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 lymphomas. In contrast, another pro-survival protein MCL1 was less expressed in this subtype, even when compared with its expression in the non-"double-hit" and "double-protein-expression" type. Furthermore, studies using two "double-hit" and "double-protein-expression" lymphoma-derived cell lines, Karpas231 and OCI-Ly8, clearly showed that a low concentration of venetoclax, but not the MCL1 inhibitor S63845, was sufficient to induce apoptosis in the two lines, compared with in other germinal center 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 B56α 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 transduction related to BCL2 and MCL1 in "double-hit" and "double-protein-expression" lymphoma cells.
具有 和 重排的所谓“双打击”和“双蛋白表达”淋巴瘤是一种罕见的成熟 B 细胞肿瘤，其特征为生发中心 B 细胞表型、MYC 和 BCL2 大量蛋白表达、疾病快速进展和预后不良。在本研究中，我们展示了 BCL2 抑制剂 venetoclax 治疗这种疾病的潜在益处。淋巴瘤组织的免疫组织化学研究证实，与其他生发中心 B 细胞样弥漫性大 B 细胞淋巴瘤相比，这种亚型中观察到 MYC 和 BCL2 的过表达更为频繁。相比之下，这种亚型中另一种生存蛋白 MCL1 的表达较少，即使与非“双打击”和“双蛋白表达”型相比也是如此。此外，使用两种“双打击”和“双蛋白表达”淋巴瘤衍生细胞系 Karpas231 和 OCI-Ly8 的研究清楚地表明，与其他生发中心 B 细胞衍生的细胞系 BJAB 和 SU-DHL10 相比，venetoclax 的低浓度而非 MCL1 抑制剂 S63845 足以诱导两种细胞系的凋亡。这些结果表明，这种类型的淋巴瘤的生存主要依赖于 BCL2，而不是 MCL1。出乎意料的是，我们发现 venetoclax 不仅破坏了 BCL2 与促凋亡蛋白 BIM 之间的相互作用，而且还导致 BCL2 的去磷酸化，进一步下调 MCL1 蛋白表达，可能是通过调节 Karpas231 和 OCI-Ly8 中的蛋白磷酸酶 2A B56α 活性。事实上，venetoclax 的低浓度诱导原发性淋巴瘤细胞发生大量凋亡，而与 venetoclax 耐药相关的 MCL1 高表达无关。Venetoclax 明显触发了“双打击”和“双蛋白表达”淋巴瘤细胞中与 BCL2 和 MCL1 相关的信号转导。
