The Tyrosine Kinase-Driven Networks of Novel Long Non-coding RNAs and Their Molecular Targets in Myeloproliferative Neoplasms.
The Tyrosine Kinase-Driven Networks of Novel Long Non-coding RNAs and Their Molecular Targets in Myeloproliferative Neoplasms.
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骨髓增生性肿瘤中酪氨酸激酶驱动的新型长非编码RNA及其分子靶标网络
DOI：
10.3389/fcell.2021.643043
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发表时间：
2021
影响因子：
5.5
通讯作者：
Huang CL
中科院分区：
文献类型：
--
作者：
Wong NK;Luo S;Chow EYD;Meng F;Adesanya A;Sun J;Ma HMH;Jin W;Li WC;Yip SP;Huang CL
最近的研究集中在长链非编码RNA（lncRNA）调节多种细胞过程如肿瘤发生的机制上。然而，这些非编码元件在基因组中的功能特性目前知之甚少。在这项研究中，我们探讨了几种机制，涉及新的lncRNA和microRNA（miRNA）轴参与药物反应的调制和骨髓增生性肿瘤（MPN）的肿瘤微环境。我们通过mRNA测序鉴定了新的lncRNA，该测序应用于用治疗性酪氨酸激酶抑制剂（TKI）治疗的BCR-ABL 1阳性和JAK 2突变型MPN衍生的白血病细胞系。在白血病细胞和从人血液分离的正常原代和多能细胞中进一步验证了新型LNC 000093的表达和序列，包括来自慢性髓性白血病（CML）患者的样品。在TKI耐药CML中验证了LNC 000093的下调，而在从TKI敏感CML病例中分离的血细胞中观察到匡威的表达模式。除BCR-ABL 1阳性CML细胞外，在BCR-ABL 1阴性MPN中进一步鉴定了JAK 2-V617 F调节的lncRNA BANCR轴驱动突变。使用MPN患者标本的进一步全基因组验证鉴定了23个独特的拷贝数变体，包括来自我们数据库的7个差异表达的lncRNA。新鉴定的LNC 000093作为miR-675- 5 p的竞争性内源RNA，通过调节RUNX 1表达逆转CML细胞中的伊马替尼耐药性。还确定了LNC 000093在外泌体H19/miR-675诱导的微环境调节中的外在功能，对VEGF表达具有显著影响。
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.
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影响因子：
2.7
作者：
Pasquier, Florence;Cabagnols, Xenia;Vainchenker, Williai
通讯作者：
Vainchenker, Williai
影响因子：
12.8
作者：
Barbui T;Thiele J;Gisslinger H;Kvasnicka HM;Vannucchi AM;Guglielmelli P;Orazi A;Tefferi A
通讯作者：
Tefferi A
影响因子：
3
作者：
Mistry J;Bateman A;Finn RD
通讯作者：
Finn RD
影响因子：
9
作者：
Lin, Ye;Jian, Zhixiang;Huang, Jianfeng
通讯作者：
Huang, Jianfeng
影响因子：
4
作者：
Liu, Yujie;Feng, Lu;Xue, Jing
通讯作者：
Xue, Jing