HMGB1 promotes differentiation syndrome by inducing hyperinflammation via MEK/ERK signaling in acute promyelocytic leukemia cells.
HMGB1 promotes differentiation syndrome by inducing hyperinflammation via MEK/ERK signaling in acute promyelocytic leukemia cells.
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HMGB1 通过 MEK/ERK 信号传导在急性早幼粒细胞白血病细胞中诱导过度炎症，从而促进分化综合征
DOI：
10.18632/oncotarget.15432
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发表时间：
2017-04-18
期刊：
影响因子：
--
通讯作者：
Yang L
中科院分区：
文献类型：
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作者：
Tang L;Chai W;Ye F;Yu Y;Cao L;Yang M;Xie M;Yang L
以全反式维甲酸（ATRA）和三氧化二砷（ATO）为基础的分化治疗急性早幼粒细胞白血病（APL），其分化综合征（DS）的发展是复杂的，可能是致命的。我们通过体外和体内模型研究了HMGB1（高迁移率组盒1）在DS中的作用。HMGB1和促炎因子IL-1β和TNF-α逐渐从ATRA和/或ATO处理的NB4和HL-60细胞中释放出来。同样，较高的血清HMGB1水平与退行性椎体滑移患者的临床状态呈正相关。外源性HMGB1促进IL-1β和TNF-α的快速释放以及ICAM-1的表达升高，但不改变细胞分化。在atra处理的DS小鼠中，外源性HMGB1也增强肺浸润，上调ICAM-1表达。药物抑制或消耗MEK1/2降低了细胞因子水平，抑制了ICAM-1的表达和HMGB1处理的NB4细胞对内皮细胞的粘附，暗示MEK/ERK信号通路参与了DS期间对HMGB1的反应。在atra诱导的NB4细胞中，hmgb1中和抗体可降低TNF-α和IL-1β的分泌，抑制ICAM-1的升高，减弱ERK1/2的激活。hmgb1中和抗体也降低了atra处理的DS模型小鼠的ICAM-1表达并降低了死亡率。这些发现表明，释放的HMGB1在退行性痴呆中起着核心作用，靶向HMGB1可能在退行性痴呆的治疗中具有治疗价值。
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.