Opposing effects of KDM6A and JDP2 on glucocorticoid sensitivity in T-ALL.
Opposing effects of KDM6A and JDP2 on glucocorticoid sensitivity in T-ALL.
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DOI：
10.1182/bloodadvances.2021006881
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发表时间：
2023-07-25
期刊：
影响因子：
7.5
通讯作者：
Wandler, Anica M.
中科院分区：
文献类型：
--
作者：
Levinson, Anya L.;Tjoa, Karensa;Huang, Benjamin;Meyer, Lauren K.;Kim, Mi-Ok;Brady, Samuel W.;Zhang, Jinghui;Shannon, Kevin;Wandler, Anica M.
KDM6A 失活使 T-ALL 细胞对糖皮质激素敏感，增强 JDP2 表达，逆转这种表型并引起耐药性。 KDM6A 和 JDP2 的改变可调节 T-ALL 细胞中糖皮质激素诱导的 NR3C1 mRNA 和糖皮质激素受体蛋白表达。糖皮质激素（GC）是急性淋巴细胞白血病（ALL）治疗的基石。尽管编码 GC 受体 (GR) 的 NR3C1 以及参与 GC 信号转导的其他基因在复发时发生突变，但适应性 GC 抵抗的其他机制尚不确定。我们移植并治疗了 10 只原发性小鼠 T 系急性淋巴细胞白血病 (T-ALL)，这些小鼠是通过使用 GC 地塞米松 (DEX) 进行逆转录病毒插入诱变引发的。来自一种此类白血病 (T-ALL 8633) 的多个不同的复发克隆表现出离散的逆转录病毒整合，从而上调 Jdp2 表达。这种白血病含有 Kdm6a 突变。在人 T-ALL 细胞系 CCRF-CEM 中，强制 JDP2 过度表达会赋予 GC 抗性，而 KDM6A 失活则出乎意料地增强了 GC 敏感性。在 KDM6A 敲除的背景下，JDP2 过表达诱导了严重的 GC 耐药性，抵消了 KDM6A 缺失带来的致敏作用。这些具有 KDM6A 缺失和 JDP2 过表达的耐药“双突变”细胞在 DEX 暴露后表现出 NR3C1 mRNA 降低和 GR 蛋白上调。对复发儿科 ALL 队列中 2 名 KDM6A 突变 T-ALL 患者的配对样本进行分析，发现 1 名患者复发时存在体细胞 NR3C1 突变，另一名患者的 JDP2 表达显着升高。总之，这些数据表明 JDP2 过表达是 T-ALL 中适应性 GC 抵抗的机制，其在功能上与 KDM6A 失活相互作用。
KDM6A inactivation sensitizes T-ALL cells to glucocorticoids, enforces JDP2 expression, reverses this phenotype, and causes resistance. Alterations in KDM6A and JDP2 modulate glucocorticoid-induced NR3C1 mRNA and glucocorticoid receptor protein expression in T-ALL cells. 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.
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影响因子：
64.5
作者：
Burgess MR;Hwang E;Mroue R;Bielski CM;Wandler AM;Huang BJ;Firestone AJ;Young A;Lacap JA;Crocker L;Asthana S;Davis EM;Xu J;Akagi K;Le Beau MM;Li Q;Haley B;Stokoe D;Sampath D;Taylor BS;Evangelista M;Shannon K
通讯作者：
Shannon K
影响因子：
20.3
作者：
Girardi T;Vicente C;Cools J;De Keersmaecker K
通讯作者：
De Keersmaecker K
影响因子：
30.8
作者：
Paugh, Steven W.;Bonten, Erik J.;Savic, Daniel;Ramsey, Laura B.;Thierfelder, William E.;Gurung, Prajwal;Malireddi, R. K. Subbarao;Actis, Marcelo;Mayasundari, Anand;Min, Jaeki;Coss, David R.;Laudermilk, Lucas T.;Panetta, John C.;McCorkle, J. Robert;Fan, Yiping;Crews, Kristine R.;Stocco, Gabriele;Wilkinson, Mark R.;Ferreira, Antonio M.;Cheng, Cheng;Yang, Wenjian;Karol, Seth E.;Fernandez, Christian A.;Diouf, Barthelemy;Smith, Colton;Hicks, J. Kevin;Zanut, Alessandra;Giordanengo, Audrey;Crona, Daniel;Bianchi, Joy J.;Holmfeldt, Linda;Mullighan, Charles G.;den Boer, Monique L.;Pieters, Rob;Jeha, Sima;Dunwell, Thomas L.;Latif, Farida;Bhojwani, Deepa;Carroll, William L.;Pui, Ching-Hon;Myers, Richard M.;Guy, R. Kiplin;Kanneganti, Thirumala-Devi;Relling, Mary V.;Evans, William E.
通讯作者：
Evans, William E.
DOI：
10.1084/jem.20170484
发表时间：
2018-07-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Mansour MR;He S;Li Z;Lobbardi R;Abraham BJ;Hug C;Rahman S;Leon TE;Kuang YY;Zimmerman MW;Blonquist T;Gjini E;Gutierrez A;Tang Q;Garcia-Perez L;Pike-Overzet K;Anders L;Berezovskaya A;Zhou Y;Zon LI;Neuberg D;Fielding AK;Staal FJT;Langenau DM;Sanda T;Young RA;Look AT
通讯作者：
Look AT
影响因子：
5.4
作者：
Wolff, L;Koller, R;Anver, MR
通讯作者：
Anver, MR