Glucocorticoid receptor gene mutations confer glucocorticoid resistance in B-cell precursor acute lymphoblastic leukemia-猫眼课题宝

DOI：

10.1016/j.jsbmb.2022.106068

发表时间：

2022-02

期刊：

The Journal of Steroid Biochemistry and Molecular Biology

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Minori Tamai;S. Kasai;K. Akahane;Thao Nguyen Thu;K. Kagami;Chiaki Komatsu;M. Abe;Atsushi Watanabe;K. Goi;Kunio Miyake;T. Inaba;J. Takita;H. Goto;M. Minegishi;S. Iwamoto;K. Sugita;T. Inukai

糖皮质激素（GC）是治疗B细胞前体急性淋巴细胞白血病（BCP-ALL）的关键药物，初始GC反应是重要的预后因素。 GC 受体在 GC 敏感性中发挥重要作用，据报道在一些 BCP-ALL 病例中发现了 GC 受体基因 NR3C1 的体细胞突变，特别是在复发时。此外，CREB 结合蛋白 (CREBBP) 和 Wolf-Hirschhorn 综合征候选 1 (WHSC1) 基因的体细胞突变与 ALL 的 GC 耐药性相关。然而，这些突变在 BCP-ALL GC 敏感性中的意义仍有待在内在基因中阐明。在本研究中，我们对 99 个 BCP-ALL 和 22 个 T-ALL 细胞系（已知在诊断时和复发时分别建立了 32 和 67 个细胞系）中的 NR3C1、WHSC1 和 CREBBP 基因进行了测序，并分别在 19 个（诊断时的 2 个细胞系和复发时的 15 个细胞系）、26 个（6 和 15 个）和 38 个（11 和 15 个）细胞系中检测到了它们的突变。值得注意的是，14 个带有 NR3C1 突变的 BCP-ALL 细胞系比那些没有突变的细胞系对 GC 的抵抗力显着增强。相反，WHSC1和CREBBP突变与GC耐药无关。然而，在NR3C1未突变的BCP-ALL细胞系中，WHSC1突变往往与GC抵抗和较低的NR3C1基因表达相关。最后，我们通过使用 CRISPR/Cas9 系统破坏 NR3C1 基因的配体结合和 DNA 结合域，成功建立了 GC 敏感的 BCP-ALL 细胞系 (697) 的 GC 抗性亚系。这些观察结果表明，NR3C1 基因以及可能的 WHSC1 基因的体细胞突变赋予 BCP-ALL GC 抗性。

Glucocorticoid (GC) is a key drug in the treatment of B-cell precursor acute lymphoblastic leukemia (BCP-ALL), and the initial GC response is an important prognostic factor. GC receptors play an essential role in GC sensitivity, and somatic mutations of the GC receptor gene,NR3C1, are reportedly identified in some BCP-ALL cases, particularly at relapse. Moreover, associations of somatic mutations of the CREB-binding protein (CREBBP) and Wolf-Hirschhorn syndrome candidate 1 (WHSC1) genes with the GC-resistance of ALL have been suggested. However, the significance of these mutations in the GC sensitivity of BCP-ALL remains to be clarified in the intrinsic genes. In the present study, we sequencedNR3C1,WHSC1, andCREBBPgenes in 99 BCP-ALL and 22 T-ALL cell lines (32 and 67 cell lines were known to be established at diagnosis and at relapse, respectively), and detected their mutations in 19 (2 cell lines at diagnosis and 15 cell lines at relapse), 26 (6 and 15), and 38 (11 and 15) cell lines, respectively. Of note, 14 BCP-ALL cell lines with theNR3C1mutations were significantly more resistant to GC than those without mutations. In contrast,WHSC1andCREBBPmutations were not associated with GC resistance. However, among theNR3C1unmutated BCP-ALL cell lines,WHSC1mutations tended to be associated with GC resistance and lowerNR3C1gene expression. Finally, we successfully established GC-resistant sublines of the GC-sensitive BCP-ALL cell line (697) by disrupting ligand binding and DNA binding domains of theNR3C1gene using the CRISPR/Cas9 system. These observations demonstrated that somatic mutations of theNR3C1gene, and possibly theWHSC1gene, confer GC resistance in BCP-ALL.

Glucocorticoid receptor gene mutations confer glucocorticoid resistance in B-cell precursor acute lymphoblastic leukemia

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