Caspase-3 controls AML1-ETO-driven leukemogenesis via autophagy modulation in a ULK1-dependent manner
2017
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
executoramong 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
ULK1as a novel substrate of
Caspase-3 and show that upregulation of
ULK1drives autophagy initiation in leukemia cells and that inhibition of
ULK1can 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 disease.
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