title: HMGB1 promotes differentiation syndrome by inducing hyperinflammation via MEK/ERK signaling in acute promyelocytic leukemia cells.
abstract: Differentiation therapy based on all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) for the treatment of acute promyelocytic leukemia (APL) is complicated by the development of differentiation syndrome (DS), which can be fatal. We examined the role of HMGB1 (high-mobility group box 1) in DS using both in vitro and in vivo models. HMGB1 and the pro-inflammatory cytokines IL-1β and TNF-α were gradually released from NB4 and HL-60 cells treated with ATRA and/or ATO. Similarly, higher serum HMGB1 levels positively correlated with the clinical status of DS patients. Exogenous HMGB1 promoted rapid release of IL-1β and TNF-α as well as elevated expression of ICAM-1, without altering cell differentiation. Exogenous HMGB1 also enhanced pulmonary infiltration and up-regulated ICAM-1 expression in the ATRA-treated DS mouse. Pharmacological inhibition or depletion of MEK1/2 reduced the cytokine levels and suppressed expression of ICAM-1 and the adhesion of HMGB1-treated NB4 cells to endothelial cells, implicating MEK/ERK signaling in the response to HMGB1 during DS. Treatment with a HMGB1-neutralizing antibody reduced secretion of TNF-α and IL-1β, arrested the elevation of ICAM-1 and blunted the activation of ERK1/2 in ATRA-induced NB4 cells. The HMGB1-neutralizing antibody also decreased ICAM-1 expression and reduced mortality in ATRA-treated DS model mice. These findings demonstrate that released HMGB1 is central to DS, and that targeting HMGB1 may be of therapeutic value in the treatment of DS.
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Tang
authors.affiliation: Department of Nuclear Medicine, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, People's Republic of China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Chai
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China.
authors.forename: Fanghua
authors.initials: F
authors.lastname: Ye
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China.
authors.forename: Minghua
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China.
authors.forename: Liangchun
authors.initials: L
authors.lastname: Yang
mesh_terms: D000293:Adolescent; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007223:Infant; D018836:Inflammation Mediators / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D020935:MAP Kinase Signaling System; D008297:Male; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D012074:Remission Induction; D023041:Xenograft Model Antitumor Assays
chemical_list: D015815:Cell Adhesion Molecules; D016207:Cytokines; D024243:HMGB1 Protein; D018836:Inflammation Mediators
keywords: HMGB1; MEK/ERK; adhesive molecule; cytokines; differentiation syndrome