慢性粒细胞白血病（CML）是一种常见的血液系统恶性肿瘤，酪氨酸激酶抑制剂（TKI）是CML的主要治疗方法。代谢信号通路的激活与 CML 细胞中 BCR::ABL1 独立的 TKI 耐药性有关。然而，代谢信号介导这种耐药性的具体机制仍不清楚。在这里，我们确定了CML细胞中谷氨酰胺合成酶（GS）与BCR::ABL1独立的伊马替尼耐药之间的一种关系。通过全转录组筛选并检测了伊马替尼耐药（IR）的CML患者的骨髓样本中的GS和PXN-AS1测序。分别使用LV上调GS表达并使用shRNA阻断GS表达，然后分别测试GS表达、Gln含量和细胞周期进程。通过尾静脉注射建立CML IR小鼠模型，通过Kaplan-Meier分析、脾重/体重比、HE染色和IHC评估CML IR小鼠模型的预后。使用shRNA阻断PXN-AS1水平，并与GS相同地在体外和体内测试PXN-AS1对CML IR细胞的影响。使用几种 RNA-RNA 工具来预测与 GS 和 PXN-AS1 结合的潜在目标 microRNA。利用RNA模拟物和RNA抑制剂探讨PXN-AS1调节miR-635或miR-635调节GS的机制。GS在伊马替尼耐药的CML患者的骨髓样本中高表达。此外，发现lncRNA PXN-AS1通过mTOR信号通路介导CML IR细胞中的GS表达和细胞周期紊乱。 PXN-AS1 通过与 miR-635 结合来调节 GS 表达。此外，PXN-AS1的敲低通过PXN-AS1/miR-635/GS/Gln/mTOR信号通路减弱了CML细胞中BCR::ABL1独立的伊马替尼耐药性。因此，PXN-AS1促进GS介导的BCR::ABL1-通过细胞周期信号通路在 CML 细胞中实现独立的伊马替尼耐药。© 2024。作者。

Chronic myeloid leukemia (CML) is a common hematological malignancy, and tyrosine kinase inhibitors (TKIs) represent the primary therapeutic approach for CML. Activation of metabolism signaling pathway has been connected with BCR::ABL1-independent TKIs resistance in CML cells. However, the specific mechanism by which metabolism signaling mediates this drug resistance remains unclear. Here, we identified one relationship between glutamine synthetase (GS) and BCR::ABL1-independent Imatinib resistance in CML cells.GS and PXN-AS1 in bone marrow samples of CML patients with Imatinib resistance (IR) were screened and detected by whole transcriptome sequencing. GS expression was upregulated using LVs and blocked using shRNAs respectively, then GS expression, Gln content, and cell cycle progression were respectively tested. The CML IR mice model were established by tail vein injection, prognosis of CML IR mice model were evaluated by Kaplan-Meier analysis, the ratio of spleen/body weight, HE staining, and IHC. PXN-AS1 level was blocked using shRNAs, and the effects of PXN-AS1 on CML IR cells in vitro and in vivo were tested the same as GS. Several RNA-RNA tools were used to predict the potential target microRNAs binding to both GS and PXN-AS1. RNA mimics and RNA inhibitors were used to explore the mechanism through which PXN-AS1 regulates miR-635 or miR-635 regulates GS.GS was highly expressed in the bone marrow samples of CML patients with Imatinib resistance. In addition, the lncRNA PXN-AS1 was found to mediate GS expression and disorder cell cycle in CML IR cells via mTOR signaling pathway. PXN-AS1 regulated GS expression by binding to miR-635. Additionally, knockdown of PXN-AS1 attenuated BCR::ABL1-independent Imatinib resistance in CML cells via PXN-AS1/miR-635/GS/Gln/mTOR signaling pathway.Thus, PXN-AS1 promotes GS-mediated BCR::ABL1-independent Imatinib resistance in CML cells via cell cycle signaling pathway.© 2024. The Author(s).