儿童复发性 B 细胞急性淋巴细胞白血病 (B-ALL) 的糖皮质激素 (GC) 耐药性是一个重要的挑战。尽管临床使用了数十年，但耐药性的机制仍然知之甚少。在此，我们报道，在 B-ALL 中，GC 通过趋化因子受体 CXCR4 激活磷脂酶 C (PLC) 介导的细胞生存途径，从而矛盾地诱导自身抵抗。我们发现 PLC 在 GC 抗性 B-ALL 中被异常激活，其抑制能够通过损害多个转录程序来诱导细胞死亡。从机制上讲，地塞米松 (Dex) 会激发 CXCR4 信号传导，从而激活 PLC 依赖性 Ca2 和蛋白激酶 C 信号传导途径，从而削弱抗癌活性。用 CXCR4 拮抗剂或 PLC 抑制剂治疗可改善 Dex 治疗的 NSG 小鼠的体内存活率。 CXCR4/PLC 轴抑制可显着逆转 B-ALL 细胞系（体外和体内）和来自 Dex 耐药性 ALL 患者的细胞中的 Dex 耐药性。我们的研究确定了 Dex 对 B-ALL 中 PLC 信号体的激活如何限制了这种化疗药物的前期疗效。© 2024。作者。

Glucocorticoid (GC) resistance in childhood relapsed B-cell acute lymphoblastic leukemia (B-ALL) represents an important challenge. Despite decades of clinical use, the mechanisms underlying resistance remain poorly understood. Here, we report that in B-ALL, GC paradoxically induce their own resistance by activating a phospholipase C (PLC)-mediated cell survival pathway through the chemokine receptor, CXCR4. We identify PLC as aberrantly activated in GC-resistant B-ALL and its inhibition is able to induce cell death by compromising several transcriptional programs. Mechanistically, dexamethasone (Dex) provokes CXCR4 signaling, resulting in the activation of PLC-dependent Ca2+ and protein kinase C signaling pathways, which curtail anticancer activity. Treatment with a CXCR4 antagonist or a PLC inhibitor improves survival of Dex-treated NSG mice in vivo. CXCR4/PLC axis inhibition significantly reverses Dex resistance in B-ALL cell lines (in vitro and in vivo) and cells from Dex resistant ALL patients. Our study identifies how activation of the PLC signalosome in B-ALL by Dex limits the upfront efficacy of this chemotherapeutic agent.© 2024. The Author(s).