Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Department of Medicine, Washington University, St. Louis, MO 63105, USA.
Cancer Cell. 2014 Apr 14;25(4):530-42. doi: 10.1016/j.ccr.2014.03.008.
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 patients with MLL-AF4 leukemia. Hence, feasible strategies to treat cancer-type and oncogene-specific cancers can be improvised through harnessing inherent tumor suppression properties of individual oncogenic fusions.
染色体易位破坏 MLL 会产生 MLL 融合蛋白，从而诱导侵袭性白血病。出乎意料的是，很少观察到高水平的 MLL 融合蛋白，这表明过多的 MLL 融合可能与恶性表型不兼容。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降低内源性 MLL 融合物的周转率，发现积累的 MLL 融合物会诱导潜在的、依赖上下文的肿瘤抑制程序。具体来说，在 MLL 前 B 淋巴样白血病中，但不是髓样白血病中，蛋白酶体抑制会触发凋亡和细胞周期停滞，分别涉及 caspase-8 激活切割 BID 和上调 p27。此外，蛋白酶体抑制对 MLL-AF4 白血病患者有初步益处。因此，可以通过利用单个致癌融合体固有的肿瘤抑制特性，即兴制定针对癌症类型和致癌基因特异性癌症的可行治疗策略。
