Integrative multi-omics analysis of long non-coding RNA regulatory networks in chronic myeloid leukemia resistance...

Treatment resistance and leukemic stem cell survival are significant challenges in managing chronic myeloid leukemia (CML). While Breakpoint Cluster Region-Abelson (BCR::ABL1) fusion drives disease initiation, emerging evidence suggests that non-coding RNAs, particularly long non-coding RNAs (lncRNAs), regulate critical cellular processes that promote leukemic transformation and treatment failure. We employed a comprehensive in silico approach integrating multiple omics platforms to investigate CML-associated lncRNAs. Candidate lncRNAs were identified by cross-referencing LncRNA Disease and LncTarD repositories, followed by validation expression analysis of data in leukemia transcriptomic cohorts. StarBase and miRWalk algorithms predicted the interaction networks between lncRNAs and microRNAs, while transcription factor (TF) binding was determined through ChIP-seq analysis and TF databases to map the regulatory networks governing lncRNA and miRNA expression. Four critical long non-coding RNAs (lncRNAs), H19, HOTAIR, MEG3, and UCA1, were differentially expressed in CML and were involved in regulating proliferation, cell death, and therapeutic response pathways. Network analysis revealed extensive regulatory interactions with microRNAs, especially hsa-miR-18a-5p and hsa-miR-106b-5p, which influence major oncogenic pathways. TFs mapping identified pivotal hubs, including MYC and STAT5A, as key regulators of lncRNA and miRNA networks, which contribute to disrupted normal growth control, and apoptotic and survival pathways in leukemic cells. This study identified a non-coding RNA interactome in CML involving lncRNAs and microRNAs that may cooperatively contribute to CML progression. These interconnected circuits offer novel insights into treatment resistance and stem cell persistence, identifying promising therapeutic targets. Future validation of these interactions may guide the development of non-coding RNA-targeted therapies for resistant CML.