Department of Pediatrics, University of California, San Francisco, CA.
Department of Epidemiology and Biostatistics, University of California, San Francisco, CA.
Blood Adv. 2023 Jul 25;7(14):3479-3484. doi: 10.1182/bloodadvances.2021006881.
Glucocorticoids (GCs) are the cornerstone of acute lymphoblastic leukemia (ALL) therapy. Although mutations in NR3C1, which encodes the GC receptor (GR), and other genes involved in GC signaling occur at relapse, additional mechanisms of adaptive GC resistance are uncertain. We transplanted and treated 10 primary mouse T-lineage acute lymphoblastic leukemias (T-ALLs) initiated by retroviral insertional mutagenesis with GC dexamethasone (DEX). Multiple distinct relapsed clones from 1 such leukemia (T-ALL 8633) exhibited discrete retroviral integrations that upregulated Jdp2 expression. This leukemia harbored a Kdm6a mutation. In the human T-ALL cell line CCRF-CEM, enforced JDP2 overexpression conferred GC resistance, whereas KDM6A inactivation unexpectedly enhanced GC sensitivity. In the context of KDM6A knockout, JDP2 overexpression induced profound GC resistance, counteracting the sensitization conferred by KDM6A loss. These resistant "double mutant" cells with combined KDM6A loss and JDP2 overexpression exhibited decreased NR3C1 mRNA and GR protein upregulation upon DEX exposure. Analysis of paired samples from 2 patients with KDM6A-mutant T-ALL in a relapsed pediatric ALL cohort revealed a somatic NR3C1 mutation at relapse in 1 patient and a markedly elevated JDP2 expression in the other. Together, these data implicate JDP2 overexpression as a mechanism of adaptive GC resistance in T-ALL, which functionally interacts with KDM6A inactivation.
糖皮质激素（GCs）是急性淋巴细胞白血病（ALL）治疗的基石。虽然 NR3C1 基因突变（编码 GC 受体（GR））和其他参与 GC 信号转导的基因在复发时发生，但适应性 GC 耐药的其他机制尚不确定。我们用 GC 地塞米松（DEX）移植并治疗了 10 种由逆转录病毒插入诱变引发的原发性小鼠 T 系急性淋巴细胞白血病（T-ALL）。来自 1 种白血病（T-ALL 8633）的多个不同复发克隆表现出离散的逆转录病毒整合，上调了 Jdp2 表达。这种白血病携带 Kdm6a 突变。在人类 T-ALL 细胞系 CCRF-CEM 中，强制 JDP2 过表达赋予 GC 耐药性，而 KDM6A 失活出人意料地增强了 GC 敏感性。在 KDM6A 敲除的情况下，JDP2 过表达诱导了强烈的 GC 耐药性，抵消了 KDM6A 缺失赋予的敏化作用。这些具有 KDM6A 缺失和 JDP2 过表达的“双重突变”耐药细胞在 DEX 暴露时表现出 NR3C1 mRNA 和 GR 蛋白上调减少。对 2 名 KDM6A 突变 T-ALL 患者的配对样本进行分析，该队列是复发儿科 ALL 队列的一部分，在 1 名患者中发现了复发时的 NR3C1 突变，而另 1 名患者的 JDP2 表达明显升高。这些数据共同表明，JDP2 过表达是 T-ALL 中适应性 GC 耐药的一种机制，它与 KDM6A 失活功能相互作用。
