Abstract
Tyrosine kinase inhibitors (TKI) have transformed chronic myeloid leukemia (CML) from a life-threatening disease into a manageable chronic condition. However, 30-50% of patients require TKI switching due to resistance or intolerance, and BCR::ABL1-independent resistance mechanisms remain the most frequent and least understood cause. Non-coding RNAs (ncRNAs) - including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) - have emerged as regulators of TKI resistance. This scoping review aimed to characterize the role of ncRNAs in TKI resistance, and to evaluate their potential as biomarkers and therapeutic targets. A systematic literature search was performed in PubMed/MEDLINE in April 2026, supplemented by manual reference searching. Of 374 identified records, 25 studies published between 2021 and 2025, plus one 2020 study identified through manual searching were included. miRNAs were the most frequently evaluated (64%), followed by lncRNAs (16%) and circRNAs (12%), with imatinib as the predominant TKI studied. Four axes were identified for miRNAs: downstream BCR::ABL1 signaling regulation, the miR-185/PAK6 axis, apoptosis and protective autophagy modulation, and drug efflux mechanisms. circRNAs and lncRNAs were found to act as competing endogenous RNAs regulating resistance via PI3K/AKT/mTOR, RAS/MAPK, and autophagy pathways. Prospective multicenter validation, particularly in countries with limited access to second- and third-generation TKIs, is a priority for future research.