title: Caspase-3 controls AML1-ETO-driven leukemogenesis via autophagy modulation in a ULK1-dependent manner.
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 in AML and demonstrate that the balance and selectivity between its substrates can dictate the pace of disease.
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL.
authors.forename: Na
authors.initials: N
authors.lastname: Man
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL.
authors.forename: Yurong
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL.|State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiao-Jian
authors.initials: XJ
authors.lastname: Sun
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL.|Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL.
authors.forename: Fan
authors.initials: F
authors.lastname: Liu
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL.
authors.forename: Guoyan
authors.initials: G
authors.lastname: Cheng
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Greenblatt
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL.
authors.forename: Camilo
authors.initials: C
authors.lastname: Martinez
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Karl
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL.
authors.forename: Koji
authors.initials: K
authors.lastname: Ando
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China; and.
authors.forename: Ming
authors.initials: M
authors.lastname: Sun
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China; and.
authors.forename: Dan
authors.initials: D
authors.lastname: Hou
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China; and.
authors.forename: Bingyi
authors.initials: B
authors.lastname: Chen
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL.|Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL.
authors.forename: Mingjiang
authors.initials: M
authors.lastname: Xu
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL.|Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL.
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Saijuan
authors.initials: S
authors.lastname: Chen
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL.|Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL.|Department of Medicine, University of Miami Miller School of Medicine, Miami, FL.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Nimer
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL.|State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL.|Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China; and.
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog / Q000037:antagonists & inhibitors / Q000378:metabolism*; D063646:Carcinogenesis / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism*; D000066673:Cell Self Renewal; D004195:Disease Models, Animal; D005333:Fetus / Q000473:pathology; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D006801:Humans; D007938:Leukemia / Q000378:metabolism* / Q000473:pathology*; D016031:Liver Transplantation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010641:Phenotype; D013379:Substrate Specificity
chemical_list: D018952:Antigens, CD34; D015514:Oncogene Proteins, Fusion; D000071189:Autophagy-Related Protein-1 Homolog; C112444:Ulk1 protein, mouse; D053148:Caspase 3