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A long noncoding RNA critically regulates Bcr-Abl-mediated cellular transformation by acting as a competitive endogenous RNA

Oncogene volume 34, pages 1768–1779 (2015)Cite this article

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Abstract

Aberrant expression of long noncoding RNAs (lncRNAs) is associated with various human cancers. However, the role of lncRNAs in Bcr-Abl-mediated chronic myeloid leukemia (CML) is unknown. In this study, we performed a comprehensive analysis of lncRNAs in human CML cells using an lncRNA cDNA microarray and identified an lncRNA termed lncRNA-BGL3 that acted as a key regulator of Bcr-Abl-mediated cellular transformation. Notably, we observed that lncRNA-BGL3 was highly induced in response to disruption of Bcr-Abl expression or by inhibiting Bcr-Abl kinase activity in K562 cells and leukemic cells derived from CML patients. Ectopic expression of lncRNA-BGL3 sensitized leukemic cells to undergo apoptosis and inhibited Bcr-Abl-induced tumorigenesis. Furthermore, transgenic (TG) mice expressing lncRNA-BGL3 were generated. We found that TG expression of lncRNA-BGL3 alone in mice was sufficient to impair primary bone marrow transformation by Bcr-Abl. Interestingly, we identified that lncRNA-BGL3 was a target of miR-17, miR-93, miR-20a, miR-20b, miR-106a and miR-106b, microRNAs that repress mRNA of phosphatase and tensin homolog (PTEN). Further experiments demonstrated that lncRNA-BGL3 functioned as a competitive endogenous RNA for binding these microRNAs to cross-regulate PTEN expression. Additionally, our experiments have begun to address the mechanism of how lncRNA-BGL3 is regulated in the leukemic cells and showed that Bcr-Abl repressed lncRNA-BGL3 expression through c-Myc-dependent DNA methylation. Taken together, these results reveal that Bcr-Abl-mediated cellular transformation critically requires silence of tumor-suppressor lncRNA-BGL3 and suggest a potential strategy for the treatment of Bcr-Abl-positive leukemia.

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Acknowledgements

We thank Dr Paul B Rothman from the School of Medicine, The Johns Hopkins University for valuable discussions. This work was supported by the National Key Technologies Research and Development Program of China (2013ZX10004-611), National Basic Research Program (973) of China (2014CB541804), Intramural grant of the Chinese Academy of Sciences (KJZD-EW-L01-3), Natural Science Foundation of China (81171943, U1305212) and Hundreds of Talents Program of Chinese Academy of Sciences 2009–2014 to J-LC.

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Authors and Affiliations

  1. CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China

    G Guo, Q Kang, X Zhu, X Wang, Y Chen, J Ouyang & J-L Chen

  2. School of Life Sciences, Anhui University, Hefei, China

    X Zhu

  3. College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, China

    Q Chen & J-L Chen

  4. Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, Beijing, China

    L Zhang

  5. Center of Oncology and Hematology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    H Tan

  6. Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

    R Chen

  7. Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA

    S Huang

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Guo, G., Kang, Q., Zhu, X. et al. A long noncoding RNA critically regulates Bcr-Abl-mediated cellular transformation by acting as a competitive endogenous RNA. Oncogene 34, 1768–1779 (2015). https://doi.org/10.1038/onc.2014.131

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