title: HMGB1 translocation is involved in the transformation of autophagy complexes and promotes chemoresistance in leukaemia.
abstract: Acute lymphoblastic leukaemia (ALL) is a common paediatric cancer and is among the most curable cancers. However, the acquisition of drug resistance is a significant obstacle to the achievement of favourable outcomes, and autophagy is regarded as a mechanism that underlies chemoresistance. In this study, RT-qPCR was used to measure the expression of HMGB1 and Beclin1 in bone marrow mononuclear cells. A CCK-8 test was conducted to assess cell viability. Western blot, immunofluorescence and transmission electron microscopic analyses were performed to evaluate the autophagy levels. Immunoprecipitation analysis was performed to detect protein-protein interactions in the autophagy complexes. We found that HMGB1 expression correlated with the clinical status of ALL. In vitro, anticancer agent-induced cytotoxic effects were associated with autophagy-related drug resistance, and these effects were ameliorated by FIP200 depletion or the application of autophagy inhibitors. Moreover, the Ulk1‑Atg13-FIP200 complex, which promotes HMGB1 trafficking, acted upstream of the HMGB1-Beclin1 and PI3KC3-Beclin1 complexes and played a critical role in autophagy. Targeting the transformation of autophagic complexes or HMGB1 translocation may suppress autophagy and consequently overcome chemoresistance in leukaemia.
authors.affiliation: Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Kong
authors.affiliation: Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China.
authors.forename: Lu-Hong
authors.initials: LH
authors.lastname: Xu
authors.affiliation: Department of Pediatrics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China.
authors.forename: Jian-Pei
authors.initials: JP
authors.lastname: Fang
authors.affiliation: Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China.
authors.forename: Hong-Gui
authors.initials: HG
authors.lastname: Xu
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001343:Autophagy; D000071186:Beclin-1; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D024243:HMGB1 Protein / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008565:Membrane Proteins / Q000235:genetics; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D021381:Protein Transport
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D008565:Membrane Proteins