尽管弥漫性大B细胞淋巴瘤(DLBCL)治疗领域近年来取得了进展，但仍有许多患者无法根治。因此，需要新的治疗策略。抗凋亡B细胞淋巴瘤2(BCL2)基因在DLBCL中常常由于染色体易位t(14;18)(q32;q21)和拷贝数变异等多种机制而发生异常。然而，仅通过选择性抑制剂venetoclax靶向BCL-2只能在少数患者中产生反应。因此，我们试图确定venetoclax的合理配伍法伴随，以增强其对DLBCL细胞的活性。通过利用功能性分析动态BH3 profiling (DBP)，我们发现DNA低甲基化药物decitabine可以增加DLBCL细胞的线粒体凋亡启动和对BCL-2的依赖。RNA测序分析揭示，decitabine抑制了DLBCL细胞系的增强型PI3K-AKT信号通路，改变了线粒体膜组成。此外，它还引起了DNA损伤反应，增加了BAX和BAK的活性。在DLBCL细胞系衍生的人源异种移植小鼠模型中，decitabine和venetoclax的联合应用协同抑制了DLBCL细胞的增殖，无论是体外还是体内。我们的研究表明，decitabine与venetoclax的联合应用是值得在DLBCL患者中进行临床探索的有前景的组合治疗方法。

Despite recent advances in the therapy of diffuse large B-cell lymphoma (DLBCL), many patients are still not cured. Therefore, new therapeutic strategies are needed. The anti-apoptotic B-cell lymphoma 2 (BCL2) gene is commonly dysregulated in DLBCL due to various mechanisms such as chromosomal translocation t(14;18)(q32;q21) and copy number alterations; however, targeting BCL-2 with the selective inhibitor, venetoclax, led to response in only a minority of patients. Thus, we sought to identify a rational combination partner of venetoclax to improve its activity against DLBCL cells. Utilizing a functional assay, dynamic BH3 profiling (DBP), we found that the DNA hypomethylating agent decitabine increased mitochondrial apoptotic priming and BCL-2 dependence in DLBCL cells. RNA sequencing analysis revealed that decitabine suppressed the pro-survival PI3K-AKT pathway and altered the mitochondria membrane composition in DLBCL cell lines. Additionally, it induced a DNA damage response and increased BAX and BAK activities. The combination of decitabine and venetoclax synergistically suppressed proliferation of DLBCL cells both in vitro and in vivo in a DLBCL cell line-derived xenograft mouse model. Our study suggests that decitabine plus venetoclax is a promising combination to explore clinically in DLBCL.