Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, People's Republic of China.
Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, No. 55, Shizhen Hai Road, Xiamen, 361003, People's Republic of China.
J Cancer Res Clin Oncol. 2023 Aug;149(9):5513-5529. doi: 10.1007/s00432-022-04473-5. Epub 2022 Dec 6.
Double-hit lymphoma (DHL) is a rare and aggressive mature B-cell malignancy with concurrent MYC and BCL2 rearrangements. When DHL becomes relapsed or refractory, it becomes resistant to the majority of therapeutic approaches and has subpar clinical results. Therefore, innovative therapeutics for this particular patient population are urgently needed.
Orelabrutinib, a new oral BTK inhibitor, combined with the Bcl-2 inhibitor venetoclax, was used to confirm the antitumor effect of DHL. Cell counting kit-8 and Annexin V-FITC/PI assays were used to examine the interaction of this combined regimen on DHL cell lines and primary lymphoma cells. RNA sequencing, EdU incorporation assay, mitochondrial membrane potential assay, and western blotting were employed to explore the molecule mechanism for the cytotoxicity of orelabrutinib with or without venetoclax against DHL cell lines.
In this study, orelabrutinib combined with venetoclax synergistically induced DHL cell death, as evidenced by the inhibition of cell proliferation, the induct of cell cycle arrest, and the promotion of cell apoptosis via the mitochondrial pathway. Orelabrutinib treatment alters genome-wide gene expression in DHL cells. The combined regimen decreases the expression of BTK and Mcl-1, potentially interfering with the activity and crosstalk of PI3K/AKT signaling and p38/MAPK signaling. In addition, the combination of orelabrutinib and venetoclax shows cytotoxic activity in primary B-lymphoma cells.
In summary, these findings reveal a novel therapy targeting BCR signaling and the Bcl-2 family for DHL patients with a poor prognosis.
双打击淋巴瘤（DHL）是一种罕见且侵袭性的成熟 B 细胞恶性肿瘤，同时存在 MYC 和 BCL2 重排。当 DHL 复发或耐药时，它对大多数治疗方法产生耐药性，临床效果较差。因此，迫切需要为这一特定患者群体提供创新的治疗方法。
新型口服 BTK 抑制剂奥来巴替尼与 Bcl-2 抑制剂维奈托克联合用于确认 DHL 的抗肿瘤作用。使用细胞计数试剂盒-8 和 Annexin V-FITC/PI 检测来评估该联合方案对 DHL 细胞系和原发性淋巴瘤细胞的相互作用。通过 RNA 测序、EdU 掺入实验、线粒体膜电位测定和 Western blot 实验，探索奥来巴替尼联合或不联合维奈托克对 DHL 细胞系的细胞毒性的分子机制。
在这项研究中，奥来巴替尼联合维奈托克协同诱导 DHL 细胞死亡，表现为抑制细胞增殖、诱导细胞周期停滞和通过线粒体途径促进细胞凋亡。奥来巴替尼处理改变了 DHL 细胞的全基因组基因表达。联合方案降低了 BTK 和 Mcl-1 的表达，可能干扰了 PI3K/AKT 信号和 p38/MAPK 信号的活性和串扰。此外，奥来巴替尼和维奈托克的联合在原发性 B 淋巴细胞瘤细胞中显示出细胞毒性活性。
总之，这些发现揭示了一种针对 BCR 信号和 Bcl-2 家族的新型治疗方法，为预后不良的 DHL 患者提供了新的治疗选择。
