Role and mechanism of ribosomal protein S3 in tyrosine kinase inhibitor resistance in chronic myeloid leukemia
- 1Key Laboratory of Molecular Diagnosis and Treatment of Hematological Diseases of Shanxi Province, Department of Hematology, The Second Hospital of Shanxi Medical University
Abstract
Introduction: Resistance to tyrosine kinase inhibitors (TKIs) remains a major cause of treatment failure in chronic myeloid leukemia (CML). This study investigated the role of ribosomal protein S3 (RPS3) in TKI resistance and its association with NF-κB signaling.
Methods: Exploratory RNA sequencing and an RNA-binding protein database were used to prioritize a candidate for subsequent clinical expression and functional analyses. RPS3 expression was examined in an independent clinical cohort and resistant cell models. RPS3 knockdown and pharmacological modulation were used to evaluate drug sensitivity, apoptosis, cell cycle distribution, and NF-κB-associated signaling.
Results: RPS3 was upregulated in clinical samples from patients with TKI resistance or poor responses and in resistant cell models. Receiver operating characteristic analysis showed that RPS3 expression discriminated between resistant/poor-response patients and good responders in the validation cohort. RPS3 knockdown lowered imatinib and nilotinib IC ₅₀ values, with increased apoptosis and G ₀ /G ₁ -phase arrest following TKI exposure. These effects were accompanied by reduced p65 phosphorylation, a lower p65 nuclear/cytoplasmic fluorescence ratio, and decreased MCL-1 and BCL-XL mRNA levels. TNF-α treatment increased TKI tolerance and reduced TKI-induced apoptosis in RPS3-knockdown cells, whereas co-treatment with BAY-11-7082 counteracted these effects. BAY-11-7082 also showed synergistic inhibitory effects with TKIs in resistant cells under the highest single agent model.
Discussion: These findings identify RPS3 as a contributor to TKI resistance in CML cell models and connect its functional effects to NF-κB-associated anti-apoptotic signaling. By integrating clinical expression data with functional and pharmacological analyses, this study supports further investigation of RPS3 as a candidate target for sensitizing resistant CML cells to TKIs.
Related
- A Novel ACLY Inhibitor Induces Transcriptional and Metabolic Reprogramming to Overcome Tyrosine kinase inhibitor Resistance in Lymphoma
- Health status impairments in tyrosine kinase inhibitor-treated chronic myeloid leukemia patients versus blood or marrow transplant survivors and non-cancer controls
- A noncanonical function of the tyrosine degradation enzyme FAH drives CDK4/6 inhibitor resistance in breast cancer
- LONGITUDINAL EXPRESSION OF MICRORNAS IN CHRONIC MYELOID LEUKEMIA FOLLOWING TYROSINE KINASE INHIBITOR DISCONTINUATION: POTENTIAL BIOMARKERS OF TREATMENT-FREE REMISSION
- EVOLUTION OF TYROSINE KINASE INHIBITOR USE AND MOLECULAR RESPONSE PATTERNS ACROSS LINES OF THERAPY IN CHRONIC MYELOID LEUKEMIA: REAL-WORLD EVIDENCE FROM BRAZIL
BibTeX
@article{sun2026role,
title = {{Role and mechanism of ribosomal protein S3 in tyrosine kinase inhibitor resistance in chronic myeloid leukemia}},
author = {Zheng Sun and Sijin Liu and Yuxin Ning and Jinwen Dang and Zhuanghui Hao and Xiaoning Wang and Bianbian Qiao and Qianni Jin and Kai Dong and Congrui Yan and Zhilei Jin and Hongwei Wang and Zhifang Xu},
journal = {Frontiers in Oncology},
year = {2026},
month = oct,
doi = {10.3389/fonc.2026.2005945},
url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.2005945/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Role and mechanism of ribosomal protein S3 in tyrosine kinase inhibitor resistance in chronic myeloid leukemia
AU - Zheng Sun
AU - Sijin Liu
AU - Yuxin Ning
AU - Jinwen Dang
AU - Zhuanghui Hao
AU - Xiaoning Wang
AU - Bianbian Qiao
AU - Qianni Jin
AU - Kai Dong
AU - Congrui Yan
AU - Zhilei Jin
AU - Hongwei Wang
AU - Zhifang Xu
PY - 2026
DA - 2026/10/29
JO - Frontiers in Oncology
DO - 10.3389/fonc.2026.2005945
UR - https://www.frontiersin.org/articles/10.3389/fonc.2026.2005945/full
AB - Introduction: Resistance to tyrosine kinase inhibitors (TKIs) remains a major cause of treatment failure in chronic myeloid leukemia (CML). This study investigated the role of ribosomal protein S3 (RPS3) in TKI resistance and its association with NF-κB signaling. Methods: Exploratory RNA sequencing and an RNA-binding protein database were used to prioritize a candidate for subsequent clinical expression and functional analyses. RPS3 expression was examined in an independent clinical cohort and resistant cell models. RPS3 knockdown and pharmacological modulation were used to evaluate drug sensitivity, apoptosis, cell cycle distribution, and NF-κB-associated signaling. Results: RPS3 was upregulated in clinical samples from patients with TKI resistance or poor responses and in resistant cell models. Receiver operating characteristic analysis showed that RPS3 expression discriminated between resistant/poor-response patients and good responders in the validation cohort. RPS3 knockdown lowered imatinib and nilotinib IC ₅₀ values, with increased apoptosis and G ₀ /G ₁ -phase arrest following TKI exposure. These effects were accompanied by reduced p65 phosphorylation, a lower p65 nuclear/cytoplasmic fluorescence ratio, and decreased MCL-1 and BCL-XL mRNA levels. TNF-α treatment increased TKI tolerance and reduced TKI-induced apoptosis in RPS3-knockdown cells, whereas co-treatment with BAY-11-7082 counteracted these effects. BAY-11-7082 also showed synergistic inhibitory effects with TKIs in resistant cells under the highest single agent model. Discussion: These findings identify RPS3 as a contributor to TKI resistance in CML cell models and connect its functional effects to NF-κB-associated anti-apoptotic signaling. By integrating clinical expression data with functional and pharmacological analyses, this study supports further investigation of RPS3 as a candidate target for sensitizing resistant CML cells to TKIs.
SN - 2234-943X
ER -