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

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.

Extracellular vesicles in hematological malignancies: EV-dence for reshaping the tumoral microenvironment

“…Importantly, IL-8 released by BM-MSCs can promote the adhesion and migration of malignant cells, enhancing their survival (76). Wong and colleagues recently demonstrated that K562-derived sEVs carrying the long non-coding RNA LNC000093 and the microRNA miR-675-5p regulate vascular endothelial growth factor (VEGF) expression in BM-MSCs (77), coinciding with the previously described angiogenic ability and high level of VEGF in CML patient plasma that contribute to the tumorigenic niche (78). The growth-suppressive miR-320 is selectively sorted in CML EVs by RNA binding protein heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), transferred to BM-MSCs and inhibits b-catenin, thereby hindering osteogenesis, remodeling of the BM niche and promoting CML progression (79).…”

Exosome-Mediated Response to Cancer Therapy: Modulation of Epigenetic Machinery

“…In renal cancer, miR-549a was found to be reduced and such lower levels were reflected in the derived exosomes that were taken up by endothelial cells and the reduced miR-549a levels resulted in de-repression of HIF-1α and VEGF ultimately leading to increased angiogenesis [ 78 ]. In support of an interplay between lncRNAs and the miRNAs, lncRNA LNC000093 was found to be downregulated while the miRNA it sponged, miR-675, is elevated in imatinib-resistant leukemia cells [ 79 ]. In summary, it is increasingly being realized that exosomes, through their epigenetic cargo, induce resistance against multiple TKIs in different human cancers ( Table 4 ).…”

Drug Resistance: The Role of Exosomal miRNA in the Microenvironment of Hematopoietic Tumors

“…Numerous intratumoral T-cells are also present in the TME of the lymphoma, representing a very heterogeneous group of immune cells composed of various subpopulations: regulatory T cells (Treg), helper T cells (Th), CD8 + T cells, and follicular helper T cells (TFH) [99]. Although the specific role of these T cells in tumorigenesis is very complex and not yet entirely clear, several studies have shown that they not only induce tumor progression through the release of cytokines and/or direct contact with them, but they also play a key role in immunosuppression, and activation of the antitumor immune response-thereby promoting an immuno-proprietary microenvironment [57,100].…”