High mobility group box 1 (HMGB1) is a prototype damage-associated molecular pattern (DAMP) that can induce inflammatory and immune responses alone as well as in combination with other molecules such as DNA. However, the intricate molecular mechanisms underlying HMGB1-DNA complex-mediated innate immune response remains largely elusive. In this study, we demonstrated that HMGB1-DNA complex initially induced absent in melanoma 2 (AIM2)-dependent inflammasome activation, and promoted rapid release of inflammasome-dependent early proinflammatory cytokines such as interleukin 1β (IL-1β). Subsequently, HMGB1-DNA complex stimulated an ATG5-dependent cellular degradation process, autophagy, which was paralleled by a cessation of AIM2 inflammasome activation and IL-1β release. These HMGB1-DNA complex-induced inflammasome activation and autophagy were both dependent on the receptor for advanced glycation endproducts (RAGE) that recognizes a wide array of ligands (including HMGB1 and DNA). Thus, autophagy may function as a negative counter-regulatory mechanism for HMGB1-DNA complex-induced inflammasome activation, and provide a checkpoint to limit the development of inflammation.

PURPOSE Arsenic combined with all-trans retinoic acid (ATRA) is the standard of care for adult acute promyelocytic leukemia (APL). However, the safety and effectiveness of this treatment in pediatric patients with APL have not been reported on the basis of larger sample sizes. METHODS We conducted a multicenter trial at 38 hospitals in China. Patients with newly diagnosed APL were stratified into two risk groups according to baseline WBC count and FLT3-ITD mutation. ATRA plus arsenic trioxide or oral arsenic without chemotherapy were administered to the standard-risk group, whereas ATRA, arsenic trioxide, or oral arsenic plus reduced-dose anthracycline were administered to the high-risk group. Primary end points were event-free survival and overall survival at 2 years. RESULTS We enrolled 193 patients with APL. After a median follow-up of 28.9 months, the 2-year overall survival rate was 99% (95% CI, 97 to 100) in the standard-risk group and 95% (95% CI, 90 to 100) in the high-risk group ( P = .088). The 2-year event-free survival was 97% (95% CI, 93 to 100) in the standard-risk group and 90% (95% CI, 83 to 96) in the high-risk group ( P = .252). The plasma levels of arsenic were significantly elevated after treatment, with a stable effective level ranging from 42.9 to 63.2 ng/mL during treatment. In addition, plasma, urine, hair, and nail arsenic levels rapidly decreased to normal 6 months after the end of treatment. CONCLUSION Arsenic combined with ATRA is effective and safe in pediatric patients with APL, although long-term follow-up is still needed.

Cluster of differentiation (CD)133 is considered to be a marker of leukemia stem cells (LSCs), which are one of the primary causes of occurrence, drug resistance and relapse of acute lymphoblastic leukemia (ALL). CD82, an adhesion molecule, performs an important role in the interaction between LSCs and their niche. The purpose of the present study was to assess CD133 and CD82 expression in patients with pediatric ALL, and to evaluate the association with the clinical data. Using flow cytometric assessment and reverse transcription-polymerase chain reaction, CD133 and CD82 expression levels were measured in the bone marrow (BM) of 37 patients with newly diagnosed (ND) pediatric ALL [ALL-ND; 30 B-cell-ALL (B-ALL) and 7 T-cell-ALL (T-ALL)], in 22 patients with complete remission pediatric ALL (ALL-CR) and in 16 age-matched children without BM disease. BM plasma CD82 concentrations were measured by ELISA. The CD82 mRNA expression level in the patients with ALL-ND was significantly higher compared with that in the controls. CD82 mRNA expression levels in pediatric patients with B cell-ALL (B-ALL) were higher than those in ALL-CR patients and controls. For T-ALL, CD82 expression in ND patients was higher than in controls. CD133 mRNA expression levels in patients with pediatric B-ALL-ND were higher than that of controls and patients with ALL-CR. The frequency of CD34+ cells in pediatric ALL was significantly higher than that in controls. Frequencies of CD34+CD133+ or CD34+CD82+ cells in pediatric ALL were higher than those in controls. A positive association was observed between CD133 and CD82 mRNA expression in patients with B-ALL. A significant association was observed between CD133 mRNA expression and the hyperdiploid karyotype. Therefore, it was considered that CD133 and CD82 may serve an important role in the evolution of pediatric ALL. CD133 and CD82 should be considered as potential markers for the prognosis of patients with ALL.