Caspase-3 controls AML1-ETO-driven leukemogenesis via autophagy modulation in a ULK1-dependent manner

Na Man, Yurong Tan, Xiao Jian Sun, Fan Liu, Guoyan Cheng, Sarah M. Greenblatt, Camilo Martinez, Daniel L. Karl, Koji Ando, Ming Sun, Dan Hou, Bingyi Chen, Mingjiang Xu, Feng-Chun Yang, Zhu Chen, Saijuan Chen, Stephen D Nimer, Lan Wang

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2782-2792
Number of pages11
JournalBlood
Volume129
Issue number20
DOIs
StatePublished - May 18 2017

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ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Man, N., Tan, Y., Sun, X. J., Liu, F., Cheng, G., Greenblatt, S. M., Martinez, C., Karl, D. L., Ando, K., Sun, M., Hou, D., Chen, B., Xu, M., Yang, F-C., Chen, Z., Chen, S., Nimer, S. D., & Wang, L. (2017). Caspase-3 controls AML1-ETO-driven leukemogenesis via autophagy modulation in a ULK1-dependent manner. Blood, 129(20), 2782-2792. https://doi.org/10.1182/blood-2016-10-745034