Long non-coding RNA PXN-AS1 promotes glutamine synthetase-mediated chronic myeloid leukemia BCR::ABL1-independent resistance to Imatinib via cell cycle signaling pathway.
Cancer Cell Int
; 24(1): 186, 2024 May 29.
Article
in En
| MEDLINE
| ID: mdl-38811958
ABSTRACT
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 BCRABL1-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 BCRABL1-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 BCRABL1-independent Imatinib resistance in CML cells via PXN-AS1/miR-635/GS/Gln/mTOR signaling pathway.CONCLUSIONS:
Thus, PXN-AS1 promotes GS-mediated BCRABL1-independent Imatinib resistance in CML cells via cell cycle signaling pathway.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
Cancer Cell Int
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
United kingdom