Proteasome inhibitors evoke latent tumor suppression programs in pro-B MLL leukemias through MLL-AF4.
Proteasome inhibitors evoke latent tumor suppression programs in pro-B MLL leukemias through MLL-AF4.
复制标题
蛋白酶体抑制剂通过 MLL-AF4 在 Pro-B MLL 白血病中激发潜在的肿瘤抑制程序
DOI：
10.1016/j.ccr.2014.03.008
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发表时间：
2014-04-14
期刊：
影响因子：
50.3
通讯作者：
Hsieh JJ
中科院分区：
文献类型：
--
作者：
Liu H;Westergard TD;Cashen A;Piwnica-Worms DR;Kunkle L;Vij R;Pham CG;DiPersio J;Cheng EH;Hsieh JJ
破坏 MLL 的染色体易位会产生 MLL 融合蛋白，从而诱发侵袭性白血病。出乎意料的是，很少观察到高水平的 MLL 融合蛋白，这表明过度的 MLL 融合可能与恶性表型不相容。在这里，我们使用临床蛋白酶体抑制剂硼替佐米和卡非佐米来减少内源性 MLL 融合的周转，并发现积累的 MLL 融合会诱导潜在的、背景依赖性肿瘤抑制程序。具体而言，在 MLL 亲 B 淋巴样白血病（而非骨髓样白血病）中，蛋白酶体抑制会引发细胞凋亡和细胞周期停滞，分别涉及 Caspase-8 对 BID 的激活裂解和 p27 的上调。此外，蛋白酶体抑制使 MLL-AF4 白血病患者初步受益。因此，可以通过利用个体致癌融合的固有肿瘤抑制特性来临时制定治疗癌症类型和致癌基因特异性癌症的可行策略。
Chromosomal translocations disrupting MLL generate MLL-fusion proteins that induce aggressive leukemias. Unexpectedly, MLL-fusion proteins are rarely observed at high levels, suggesting excessive MLL-fusions may be incompatible with a malignant phenotype. Here, we used clinical proteasome inhibitors, bortezomib and carfilzomib, to reduce the turnover of endogenous MLL-fusions and discovered that accumulated MLL-fusions induce latent, context-dependent tumor suppression programs. Specifically, in MLL pro-B lymphoid, but not myeloid, leukemias, proteasome inhibition triggers apoptosis and cell cycle arrest involving activation cleavage of BID by Caspase-8 and upregulation of p27, respectively. Furthermore, proteasome inhibition conferred preliminary benefit to MLL-AF4 leukemia patients. Hence, feasible strategies to treat cancer-type and oncogene specific cancers can be improvised through harnessing inherent tumor suppression properties of individual oncogenic fusions.