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

Wong, Nonthaphat Kent1; Luo, Shumeng1; Chow, Eudora Y. D.2; Meng, Fei1; Adesanya, Adenike1; Sun, Jiahong1,3; Ma, Herman M. H.1,2; Jin, Wenfei3; Li, Wan-Chun4; Yip, Shea Ping1; Huang, Chien-Ling1

2021-04-01

10.3389/fcell.2021.643043

Frontiers in Cell and Developmental Biology   影响因子和分区

2296-634X

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.

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

SCI

英语

其他

Hong Kong Polytechnic University[YBX3] ; National Natural Science Foundation of China[31701192]

Cell Biology ; Developmental Biology

Cell Biology ; Developmental Biology

WOS:000684984700002

FRONTIERS MEDIA SA

Web of Science

1.Hong Kong Polytech Univ, Dept Hlth Technol & Informat, Kowloon, Hong Kong, Peoples R China
2.United Christian Hosp, Dept Pathol, Kwun Tong, Hong Kong, Peoples R China
3.Southern Univ Sci & Technol, Dept Biol, Shenzhen, Peoples R China
4.Natl Yang Ming Chiao Tung Univ, Coll Dent, Inst Oral Biol, Taipei, Taiwan

Wong, Nonthaphat Kent,Luo, Shumeng,Chow, Eudora Y. D.,et al. The Tyrosine Kinase-Driven Networks of Novel Long Non-coding RNAs and Their Molecular Targets in Myeloproliferative Neoplasms[J]. Frontiers in Cell and Developmental Biology,2021,9.

Wong, Nonthaphat Kent.,Luo, Shumeng.,Chow, Eudora Y. D..,Meng, Fei.,Adesanya, Adenike.,...&Huang, Chien-Ling.(2021).The Tyrosine Kinase-Driven Networks of Novel Long Non-coding RNAs and Their Molecular Targets in Myeloproliferative Neoplasms.Frontiers in Cell and Developmental Biology,9.

Wong, Nonthaphat Kent,et al."The Tyrosine Kinase-Driven Networks of Novel Long Non-coding RNAs and Their Molecular Targets in Myeloproliferative Neoplasms".Frontiers in Cell and Developmental Biology 9(2021).