Hypomethylating agent decitabine sensitizes diffuse large B-cell lymphoma to venetoclax.
Hypomethylating agent decitabine sensitizes diffuse large B-cell lymphoma to venetoclax.
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DOI：
10.3324/haematol.2023.283245
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发表时间：
2024-01-01
期刊：
影响因子：
10.1
通讯作者：
Davids, Matthew S.
中科院分区：
文献类型：
--
作者：
Zhu, Fen;Crombie, Jennifer L.;Ni, Wei;Hoang, Nguyet-Minh;Garg, Swati;Hackett, Liam;Chong, Stephen J. F.;Collins, Mary C.;Rui, Lixin;Griffin, James;Davids, Matthew S.
尽管弥漫性大B细胞淋巴瘤（DLBCL）的治疗取得了最新进展，但许多患者仍未治愈。因此，需要新的治疗策略。抗凋亡B细胞淋巴瘤2（BCL 2）基因通常在DLBCL中失调，这是由于各种机制，如染色体易位t（14;18）（q32;q21）和拷贝数改变;然而，用选择性抑制剂维奈托克靶向BCL-2，仅在少数患者中产生反应。因此，我们试图确定一个合理的组合伙伴维奈托克，以提高其对DLBCL细胞的活性。利用功能测定，动态BH 3谱，我们发现，DNA低甲基化剂地西他滨增加DLBCL细胞中的线粒体凋亡引发和BCL-2依赖性。RNA测序分析显示，地西他滨抑制促存活PI 3 K-AKT通路，并改变DLBCL细胞系中的线粒体膜组成。此外，它诱导DNA损伤反应，并增加BAX和巴克活性。地西他滨和维奈托克的组合在DLBCL细胞系衍生的异种移植小鼠模型中在体外和体内协同抑制DLBCL细胞的增殖。我们的研究表明，地西他滨联合维奈托克是一个有前途的联合应用，以探索临床DLBCL。
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, 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.
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影响因子：
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