Caspase-3 controls AML1-ETO-driven leukemogenesis via autophagy modulation in a ULK1 dependent manner.展开
作者:Man, Na(#)，Tan, Yurong，Sun, Xiao-Jian，Liu, Fan，Cheng, Guoyan，Greenblatt, Sarah，Martinez, Camilo，Karl, Daniel L，Ando, Koji，Sun, Ming，Hou, Dan，Chen, Bingyi，Xu, Mingjiang，Yang, Feng-Chun，Chen, Zhu，Chen, Saijuan，Nimer, Stephen D，Wang, Lan(*)
Blood 卷:129 期:20 页:2782-2792 发表年份:2017
摘要:AML1-ETO (AE), a fusion oncoprotein, generated by the t(8;21), can trigger acute myeloid leukemia (AML) in collaboration with mutations including c-Kit, ASXL1/2, FLT3, N-RAS, and K-RAS. Caspase-3, a key executor among its family, plays multiple roles in cellular processes, including hematopoietic development and leukemia progression. Caspase-3 was revealed to directly cleave AE in vitro, suggesting that AE may accumulate in a Caspase-3 compromised background and thereby accelerate leukemogenesis. Therefore, we developed a Caspase-3 knockout genetic mouse model of AML and found that loss of Caspase-3 actually delayed AML1-ETO9a (AE9a)-driven leukemogenesis, indicating that Caspase-3 may play distinct roles in the initiation and/or progression of AML. We report here that loss of Caspase-3 triggers a conserved, adaptive mechanism, namely autophagy (or macroautophagy), that acts to limit AE9a-driven leukemia. Furthermore, we identify ULK1 as a novel substrate of Caspase-3 and show that upregulation of ULK1 drives autophagy initiation in leukemia cells and that inhibition of ULK1 can rescue the phenotype induced by Caspase-3 deletion in vitro and in vivo Collectively, these data highlight Caspase-3 as an important regulator of autophagy in AML and demonstrate that the balance and selectivity between its substrates can dictate the pace of...