Maximal killing of lymphoma cells by DNA damage-inducing therapy requires not only the p53 targets Puma and Noxa, but also Bim
Maximal killing of lymphoma cells by DNA damage-inducing therapy requires not only the p53 targets Puma and Noxa, but also Bim
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DOI：
10.1182/blood-2010-04-280818
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发表时间：
2010-12-09
期刊：
影响因子：
20.3
通讯作者：
Scott, Clare L.
中科院分区：
文献类型：
--
作者：
Happo, Lina;Cragg, Mark S.;Scott, Clare L.
DNA 损伤化疗是癌症治疗的支柱，尽管目前尚不清楚此类治疗如何杀死肿瘤细胞。在非转化淋巴样细胞中，Puma 和 Noxa 两种促凋亡 p53 靶基因的联合缺失，与 p53 本身的缺失一样，诱导了对 DNA 损伤的抵抗力。然而，在 E mu-Myc 淋巴瘤中，同时缺乏 Puma 和 Noxa 并不比单独缺乏 Puma 产生更大的耐药性。第三个仅包含 B 细胞淋巴瘤 2 同源结构域 (BH)3 的基因 Bim 虽然不是直接的 p53 靶标，但在引起 DNA 损伤的 E mu-Myc 淋巴瘤中表达上调，并且 Bim 水平的敲低显着增加了 E mu-Myc/Puma(-/-)Noxa(-/-) 淋巴瘤的体外和体内耐药性。值得注意的是，来自 Noxa(-/-)Puma(-/-)Bim(-/-) 小鼠的 c-MYC 驱动的淋巴瘤细胞系与缺乏 p53 的细胞系具有相同的耐药性。因此，Puma、Noxa 和 Bim 的组合作用对于淋巴瘤细胞对 2 种常用的 DNA 损伤性化疗药物的最佳凋亡反应至关重要，因此将 Bim 确定为临床治疗结果的额外生物标志物。 （血。2010；116(24):5256-5267）
DNA-damaging chemotherapy is the backbone of cancer treatment, although it is not clear how such treatments kill tumor cells. In nontransformed lymphoid cells, the combined loss of 2 proapoptotic p53 target genes, Puma and Noxa, induces as much resistance to DNA damage as loss of p53 itself. In E mu-Myc lymphomas, however, lack of both Puma and Noxa resulted in no greater drug resistance than lack of Puma alone. A third B-cell lymphoma-2 homology domain (BH)3-only gene, Bim, although not a direct p53 target, was up-regulated in E mu-Myc lymphomas incurring DNA damage, and knockdown of Bim levels markedly increased the drug resistance of E mu-Myc/Puma(-/-)Noxa(-/-) lymphomas both in vitro and in vivo. Remarkably, c-MYC-driven lymphoma cell lines from Noxa(-/-)Puma(-/-)Bim(-/-) mice were as resistant as those lacking p53. Thus, the combinatorial action of Puma, Noxa, and Bim is critical for optimal apoptotic responses of lymphoma cells to 2 commonly used DNA-damaging chemotherapeutic agents, identifying Bim as an additional biomarker for treatment outcome in the clinic. (Blood. 2010;116(24):5256-5267)