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 Citations (Scopus)

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

Fingerprint

Autophagy
Caspase 3
Modulation
Acute Myeloid Leukemia
Leukemia
Oncogene Proteins
Genetic Models
Substrates
Knockout Mice
Up-Regulation
Fusion reactions
Phenotype
Mutation

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Caspase-3 controls AML1-ETO-driven leukemogenesis via autophagy modulation in a ULK1-dependent manner. / Man, Na; Tan, Yurong; Sun, Xiao Jian; Liu, Fan; Cheng, Guoyan; Greenblatt, Sarah M.; 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.

In: Blood, Vol. 129, No. 20, 18.05.2017, p. 2782-2792.

Research output: Contribution to journalArticle

Man, N, Tan, Y, Sun, XJ, Liu, F, Cheng, G, Greenblatt, SM, Martinez, C, Karl, DL, Ando, K, Sun, M, Hou, D, Chen, B, Xu, M, Yang, F-C, Chen, Z, Chen, S, Nimer, SD & Wang, L 2017, 'Caspase-3 controls AML1-ETO-driven leukemogenesis via autophagy modulation in a ULK1-dependent manner', Blood, vol. 129, no. 20, pp. 2782-2792. https://doi.org/10.1182/blood-2016-10-745034
Man, Na ; Tan, Yurong ; Sun, Xiao Jian ; Liu, Fan ; Cheng, Guoyan ; Greenblatt, Sarah M. ; 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. / Caspase-3 controls AML1-ETO-driven leukemogenesis via autophagy modulation in a ULK1-dependent manner. In: Blood. 2017 ; Vol. 129, No. 20. pp. 2782-2792.
@article{8691037ad7d247cc84e09ae3ab0e13af,
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 inAMLand demonstrate that the balance and selectivity between its substrates can dictate the pace of disease.",
author = "Na Man and Yurong Tan and Sun, {Xiao Jian} and Fan Liu and Guoyan Cheng and Greenblatt, {Sarah M.} and Camilo Martinez and Karl, {Daniel L.} and Koji Ando and Ming Sun and Dan Hou and Bingyi Chen and Mingjiang Xu and Feng-Chun Yang and Zhu Chen and Saijuan Chen and Nimer, {Stephen D} and Lan Wang",
year = "2017",
month = "5",
day = "18",
doi = "10.1182/blood-2016-10-745034",
language = "English (US)",
volume = "129",
pages = "2782--2792",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "20",

}

TY - JOUR

T1 - Caspase-3 controls AML1-ETO-driven leukemogenesis via autophagy modulation in a ULK1-dependent manner

AU - Man, Na

AU - Tan, Yurong

AU - Sun, Xiao Jian

AU - Liu, Fan

AU - Cheng, Guoyan

AU - Greenblatt, Sarah M.

AU - Martinez, Camilo

AU - Karl, Daniel L.

AU - Ando, Koji

AU - Sun, Ming

AU - Hou, Dan

AU - Chen, Bingyi

AU - Xu, Mingjiang

AU - Yang, Feng-Chun

AU - Chen, Zhu

AU - Chen, Saijuan

AU - Nimer, Stephen D

AU - Wang, Lan

PY - 2017/5/18

Y1 - 2017/5/18

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85019705225&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019705225&partnerID=8YFLogxK

U2 - 10.1182/blood-2016-10-745034

DO - 10.1182/blood-2016-10-745034

M3 - Article

C2 - 28381396

AN - SCOPUS:85019705225

VL - 129

SP - 2782

EP - 2792

JO - Blood

JF - Blood

SN - 0006-4971

IS - 20

ER -