威尼斯人
癸他滨
癌症研究
弥漫性大B细胞淋巴瘤
阿扎胞苷
低甲基化剂
淋巴瘤
白血病
生物
医学
DNA甲基化
内科学
慢性淋巴细胞白血病
基因
遗传学
基因表达
作者
Fen Zhu,Jennifer L. Crombie,Wei Ni,Nguyet-Minh Hoang,Swati Garg,Liam Hackett,Siew Meng Chong,Mary C. Collins,Rui Li,James D. Griffin,Matthew S. Davids
出处
期刊:Haematologica
[Ferrata Storti Foundation]
日期:2023-08-03
被引量:2
标识
DOI:10.3324/haematol.2023.283245
摘要
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.
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