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The Tyrosine Kinase-Driven Networks of Novel Long Non-coding RNAs and Their Molecular Targets in Myeloproliferative
Nonthaphat Kent Wong1, Shumeng Luo1, Eudora Y D Chow2
1Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon, Hong Kong.
Abstract:
Recent research has focused on the mechanisms by which long non-coding RNAs (lncRNAs) modulate diverse cellular processes such as tumorigenesis. However, the functional characteristics of these non-coding elements in the genome are poorly understood at present. In this study, we have explored several mechanisms that involve the novel lncRNA and microRNA (miRNA) axis participating in modulation of drug response and the tumor microenvironment of myeloproliferative neoplasms (MPNs). We identified novel lncRNAs via mRNA sequencing that was applied to leukemic cell lines derived from BCR-ABL1-positive and JAK2-mutant MPNs under treatment with therapeutic tyrosine kinase inhibitors (TKI). The expression and sequence of novel LNC000093 were further validated in both leukemic cells and normal primary and pluripotent cells isolated from human blood, including samples from patients with chronic myelogenous leukemia (CML). Downregulation of LNC000093 was validated in TKI-resistant CML while a converse expression pattern was observed in blood cells isolated from TKI-sensitive CML cases. In addition to BCR-ABL1-positive CML cells, the driver mutation JAK2-V617F-regulated lncRNA BANCR axis was further identified in BCR-ABL1-negative MPNs. Further genome-wide validation using MPN patient specimens identified 23 unique copy number variants including the 7 differentially expressed lncRNAs from our database. The newly identified LNC000093 served as a competitive endogenous RNA for miR-675-5p and reversed the imatinib resistance in CML cells through regulating RUNX1 expression. The extrinsic function of LNC000093 in exosomal H19/miR-675-induced modulation for the microenvironment was also determined with significant effect on VEGF expression.
Insights
This study identifies a novel long non-coding RNA (lncRNA), LNC000093, that plays a crucial role in drug resistance and the tumor microenvironment of myeloproliferative neoplasms (MPNs), offering new therapeutic targets.
Area of Science:
- * Molecular Biology
- * Oncology
- * Genetics
Background:
- * Long non-coding RNAs (lncRNAs) are increasingly recognized for their roles in cellular processes, including cancer development.
- * The specific functions of many lncRNAs, particularly in myeloproliferative neoplasms (MPNs), remain largely uncharacterized.
- * Understanding lncRNA mechanisms is crucial for developing novel therapeutic strategies against MPNs.
Purpose of the Study:
- * To investigate the role of novel lncRNAs and microRNAs (miRNAs) in modulating drug response and the tumor microenvironment in MPNs.
- * To identify specific lncRNAs involved in tyrosine kinase inhibitor (TKI) resistance in chronic myelogenous leukemia (CML).
- * To elucidate the functional mechanisms of identified lncRNAs in MPN pathogenesis.
Main Methods:
- * mRNA sequencing was employed to identify novel lncRNAs in TKI-treated leukemic cell lines from MPN patients.
- * Expression levels of LNC000093 were validated in patient-derived cells and tissues.
- * Molecular mechanisms, including competitive endogenous RNA (ceRNA) activity and exosomal transfer, were investigated.
Main Results:
- * A novel lncRNA, LNC000093, was identified and its expression inversely correlated with TKI resistance in CML.
- * LNC000093 acts as a ceRNA for miR-675-5p, reversing imatinib resistance by regulating RUNX1.
- * LNC000093 influences the tumor microenvironment via exosomal H19/miR-675, affecting VEGF expression.
Conclusions:
- * The novel lncRNA LNC000093 is a key regulator of drug response and tumor microenvironment modulation in MPNs.
- * LNC000093 represents a potential therapeutic target for overcoming TKI resistance in CML.
- * Further research into lncRNA-miRNA interactions offers promising avenues for MPN treatment.
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