Resistance to glucocorticoids (GCs), the common agents for remission induction in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), poses a significant therapeutic hurdle. Therefore, dissecting the mechanisms shaping GC resistance could lead to new treatment modalities. Here, we showed that CD9- BCP-ALL cells were preferentially resistant to prednisone and dexamethasone over other standard cytotoxic agents. Concordantly, we identified significantly more poor responders to the prednisone prephase among BCP-ALL patients with a CD9- phenotype, especially for those with adverse presenting features including older age, higher white cell count and BCR-ABL1. Furthermore, gain- and loss-of-function experiments dictated a definitive functional linkage between CD9 expression and GC susceptibility, as demonstrated by the reversal and acquisition of relative GC resistance in CD9low and CD9high BCP-ALL cells, respectively. Despite physical binding to the GC receptor NR3C1, CD9 did not alter its expression, phosphorylation or nuclear translocation but potentiated the induction of GC-responsive genes in GCresistant cells. Importantly, the MEK inhibitor trametinib exhibited higher synergy with GCs against CD9- than CD9+ lymphoblasts to reverse drug resistance in vitro and in vivo. Collectively, our results elucidate a previously unrecognized regulatory function of CD9 in GC sensitivity, and inform new strategies for management of children with resistant BCP-ALL.

中文翻译：

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CD9 影响儿童 B 细胞前体急性淋巴细胞白血病的糖皮质激素敏感性。

糖皮质激素 (GC) 是儿童 B 细胞前体急性淋巴细胞白血病 (BCP-ALL) 缓解诱导的常用药物，对糖皮质激素 (GC) 的耐药性构成了重大的治疗障碍。因此，剖析形成 GC 耐药性的机制可能会带来新的治疗方式。在这里，我们表明 CD9-BCP-ALL 细胞比其他标准细胞毒性药物优先对泼尼松和地塞米松产生耐药性。一致地，我们在具有 CD9-表型的 BCP-ALL 患者中发现了对泼尼松前期反应明显更差的患者，特别是那些具有不良表现特征（包括年龄较大、白细胞计数较高和 BCR-ABL1）的患者。此外，功能获得和功能丧失实验表明 CD9 表达和 GC 易感性之间存在明确的功能联系，CD9low 和 CD9high BCP-ALL 细胞中相对 GC 抗性的逆转和获得分别证明了这一点。尽管与 GC 受体 NR3C1 物理结合，CD9 并没有改变其表达、磷酸化或核转位，而是增强了 GC 抗性细胞中 GC 响应基因的诱导。重要的是，与 CD9+ 淋巴细胞相比，MEK 抑制剂曲美替尼 (Trametinib) 与针对 CD9- 的 GC 表现出更高的协同作用，可在体外和体内逆转耐药性。总的来说，我们的结果阐明了 CD9 在 GC 敏感性中以前未被认识的调节功能，并为治疗耐药 BCP-ALL 儿童的新策略提供了信息。