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论文题目: Caspase-3 controls AML1-ETO-driven leukemogenesis via autophagy modulation in a ULK1-dependent manner
英文论文题目: Caspase-3 controls AML1-ETO-driven leukemogenesis via autophagy modulation in a ULK1-dependent manner
第一作者: Man, N; Tan, YR; Sun, XJ; Liu, F; Cheng, GY; Greenblatt, SM; Martinez, C; Karl, DL; Ando, K; Sun, M; Hou, D; Chen, BY; Xu, MJ; Yang, FC; Chen, Z; Chen, SJ; Nimer, SD; Wang, L
英文第一作者: Man, N; Tan, YR; Sun, XJ; Liu, F; Cheng, GY; Greenblatt, SM; Martinez, C; Karl, DL; Ando, K; Sun, M; Hou, D; Chen, BY; Xu, MJ; Yang, FC; Chen, Z; Chen, SJ; Nimer, SD; Wang, L
联系作者: Wang, L (reprint author), Shanghai Inst Biol Sci, 320 Yueyang Rd, Shanghai 200031, Peoples R China.
英文联系作者: Wang, L (reprint author), Shanghai Inst Biol Sci, 320 Yueyang Rd, Shanghai 200031, Peoples R China.
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发表年度: 2017
卷: 129
期: 20
页码: 2782-2792
摘要: AML1-ETO (AE), a fusion oncoprotein generated by 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), which 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 inAMLand demonstrate that the balance and selectivity between its substrates can dictate the pace of disease.
英文摘要: AML1-ETO (AE), a fusion oncoprotein generated by 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), which 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 inAMLand demonstrate that the balance and selectivity between its substrates can dictate the pace of disease.
刊物名称: BLOOD
英文刊物名称: BLOOD
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学科: Hematology
英文学科: Hematology
影响因子: 13.164
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论文类别: Article
英文论文类别: Article
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