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

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

doi:10.3389/fcell.2021.643043

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.

Highlights

Myeloproliferative neoplasms (MPNs) are characterized by overproduction of blood cells of myeloid lineage stemming from aberrant clonal proliferation of hematopoietic stem cells
We have made considerable efforts to broaden our understanding of the molecular basis of both BCR-ABL1-pos and BCR-ABL1-neg myeloproliferative neoplasms (MPNs). By targeting both known and novel tyrosine kinasemediated Long non-coding RNAs (lncRNAs)-miRNA pathways associated with chronic myelogenous leukemia (CML) and other MPNs, we evaluated the biological significance of their regulatory functions in drug sensitivity and early hematopoietic gene expression
Recent research has reported the involvement of some lncRNAs in BCR-ABL1-positive CML and drug resistance, including H19, BGL-3 UCA1 and SNHG5 (Guo et al, 2014, 2015; He et al, 2017; Xiao et al, 2017)

Summary

Introduction

Myeloproliferative neoplasms (MPNs) are characterized by overproduction of blood cells of myeloid lineage stemming from aberrant clonal proliferation of hematopoietic stem cells. H19 and BGL-3 are early identified lncRNAs implicated in the pathogenesis of BCR-ABL1-dependent CML (Guo et al, 2014, 2015). The lncRNA HULC promotes CML cell proliferation by regulating the PI3K/AKT pathway and its expression is positively correlated with clinical stage of CML (Lu et al, 2017). Another lncRNA, HAND2AS1, is downregulated in CML, and shown to inhibit cell proliferation and enhance apoptosis by removing miRNA-1275 (Yang et al, 2019)

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