The Tyrosine Kinase-Driven Networks of Novel Long Non-coding RNAs and Their Molecular Targets in Myeloproliferative Neoplasms

Nonthaphat Kent Wong, Shumeng Luo, Eudora Y.D. Chow, Fei Meng, Adenike Adesanya, Jiahong Sun, Herman M.H. Ma, Wenfei Jin, Wan Chun Li, Shea Ping Yip, Chien Ling Huang

Research output: Journal article publicationJournal articleAcademic researchpeer-review

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.

Original languageEnglish
Article number643043
JournalFrontiers in Cell and Developmental Biology
Volume9
DOIs
Publication statusPublished - 3 Aug 2021

Keywords

  • chronic myelogenous leukemia
  • long non-coding RNAs
  • molecular targets
  • myeloproliferative neoplasms
  • tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

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