title: Targeting AMPK-ULK1-mediated autophagy for combating BET inhibitor resistance in acute myeloid leukemia stem cells.
abstract: 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 (LSCs) to BET inhibitors remains a major challenge. In this study, we evaluated the mechanisms underlying LSC resistance to the BET inhibitor JQ1. We evaluated the levels of apoptosis and macroautophagy/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. 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 BECN1/Beclin 1, increased LC3 lipidation, formation of autophagosomes, and downregulation of SQSTM1/p62. Inhibition of autophagy by pharmacological inhibitors or knockdown of BECN1 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 (p-Thr172)-ULK1 (p-Ser555) pathway was found to be associated with JQ1-induced autophagy in resistant cells. AMPK inhibition using the pharmacological inhibitor compound C or by knockdown of PRKAA/AMPKα suppressed autophagy and promoted JQ1-induced apoptosis in AML LSCs. These findings revealed that prosurvival autophagy was one of the mechanisms involved in the resistance of 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.
authors.affiliation: a 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: b Avison Biomedical Research Center , Yonsei University College of Medicine , Seoul , Korea.
authors.forename: Ju-In
authors.initials: JI
authors.lastname: Eom
authors.affiliation: b Avison Biomedical Research Center , Yonsei University College of Medicine , Seoul , Korea.
authors.forename: Hoi-Kyung
authors.initials: HK
authors.lastname: Jeung
authors.affiliation: a 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: a 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: a 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: a Division of Hematology, Department of Internal Medicine , Yonsei University College of Medicine , Seoul , Korea.
authors.forename: Yoo Hong
authors.initials: YH
authors.lastname: Min
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D000071189:Autophagy-Related Protein-1 Homolog / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000473:pathology*; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000473:pathology* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D000071189:Autophagy-Related Protein-1 Homolog; D055372:AMP-Activated Protein Kinases
keywords: AMPK-ULK1; BET inhibitor; autophagy; leukemia stem cells; resistance