Long non-coding RNA <i>PXN-AS1</i> promotes glutamine synthetase-mediated chronic myeloid leukemia BCR::ABL1-independent resistance to Imatinib via cell cycle signaling pathway

作者全名：Li, Yifei; Yuan, Shiyi; Zhou, Ying; Zhou, Jingwen; Zhang, Xuan; Zhang, Ping; Xiao, Wenrui; Zhang, Ying; Deng, Jianchuan; Lou, Shifeng

作者地址：[Li, Yifei; Yuan, Shiyi; Zhou, Ying; Zhou, Jingwen; Zhang, Ping; Xiao, Wenrui; Zhang, Ying; Deng, Jianchuan; Lou, Shifeng] Chongqing Med Univ, Affiliated Hosp 2, Dept Hematol, Chongqing 400010, Peoples R China; [Zhang, Xuan] Third Mil Med Univ, Army Med Univ, Southwest Hosp, Dept Oncol, Chongqing 400316, Peoples R China

通信作者：Zhang, Y; Deng, JC; Lou, SF (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Hematol, Chongqing 400010, Peoples R China.

来源：CANCER CELL INTERNATIONAL

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001235332200001

JCR分区：Q1

影响因子：5.3

年份：2024

卷号：24

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：CML; GS; PXN-AS1; BCR::ABL1-independent resistance; Cell cycle

摘要：Background 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. Methods 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. Results 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. Conclusions Thus, PXN-AS1 promotes GS-mediated BCR::ABL1-independent Imatinib resistance in CML cells via cell cycle signaling pathway.

基金机构：National Natural Science Foundation of China

基金资助正文：The authors would like to express their gratitude to EditSprings (https://www.editsprings.cn) for the expert linguistic services provided.