title: AMPK-ULK1-Mediated Autophagy Confers Resistance to BET Inhibitor JQ1 in Acute Myeloid Leukemia Stem Cells.
abstract: Purpose:Bromodomain and extraterminal domain (BET) inhibitors are promising epigenetic agents for the treatment of various subsets of acute myeloid leukemia (AML). However, the resistance of leukemia stem cells (LSC) to BET inhibitors remains a major challenge. In this study, we evaluated the mechanisms underlying LSC resistance to the BET inhibitor JQ1.Experimental Design:We evaluated the levels of apoptosis and autophagy induced by JQ1 in LSC-like leukemia cell lines and primary CD34+CD38-leukemic blasts obtained from AML cases with normal karyotype without recurrent mutations.Results:JQ1 effectively induced apoptosis in a concentration-dependent manner in JQ1-sensitive AML cells. However, in JQ1-resistant AML LSCs, JQ1 induced little apoptosis and led to upregulation of beclin-1, increased LC3-II lipidation, formation of autophagosomes, and downregulation of p62/SQSTM1. Inhibition of autophagy by pharmacologic inhibitors or knockdown of beclin-1 using specific siRNA enhanced JQ1-induced apoptosis in resistant cells, indicating that prosurvival autophagy occurred in these cells. Independent of mTOR signaling, activation of the AMPK (pThr172)/ULK1 (pSer555) pathway was found to be associated with JQ1-induced autophagy in resistant cells. AMPK inhibition using the pharmacologic inhibitor compound C or by knockdown of AMPKα suppressed autophagy and promoted JQ1-induced apoptosis in AML LSCs.Conclusions:These findings revealed that prosurvival autophagy was one of the mechanisms involved in the resistance AML LSCs to JQ1. Targeting the AMPK/ULK1 pathway or inhibition of autophagy could be an effective therapeutic strategy for combating resistance to BET inhibitors in AML and other types of cancer.Clin Cancer Res; 23(11); 2781-94. ©2016 AACR.
authors.affiliation: Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Jang
authors.affiliation: Avison Biomedical Research Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Ju-In
authors.initials: JI
authors.lastname: Eom
authors.affiliation: Avison Biomedical Research Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hoi-Kyung
authors.initials: HK
authors.lastname: Jeung
authors.affiliation: Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: June-Won
authors.initials: JW
authors.lastname: Cheong
authors.affiliation: Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jung Yeon
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jin Seok
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. minbrmmd@yuhs.ac.
authors.forename: Yoo Hong
authors.initials: YH
authors.lastname: Min
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D000071189:Autophagy-Related Protein-1 Homolog / Q000235:genetics*; D001381:Azepines / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009363:Neoplasm Proteins; D014411:Neoplastic Stem Cells / Q000187:drug effects; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000235:genetics; D014230:Triazoles / Q000008:administration & dosage*; D000092468:Bromodomain Containing Proteins
chemical_list: D055372:AMP-Activated Protein Kinases; D000071189:Autophagy-Related Protein-1 Homolog; D001381:Azepines; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D014230:Triazoles; C561695:(+)-JQ1 compound; C000624329:bromodomain and extra-terminal domain protein, human; D000092468:Bromodomain Containing Proteins; C484754:ULK1 protein, human; C526180:PRKAA1 protein, human