A long noncoding RNA critically regulates Bcr-Abl-mediated cellular transformation by acting as a competitive endogenous RNA.
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.
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
G
G
Guo
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
Q
Q
Kang
1] CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China [2] School of Life Sciences, Anhui University, Hefei, China.
X
X
Zhu
College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, China.
Q
Q
Chen
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
X
X
Wang
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
Y
Y
Chen
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
J
J
Ouyang
Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, Beijing, China.
L
L
Zhang
Center of Oncology and Hematology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
H
H
Tan
Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
R
R
Chen
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
S
S
Huang
1] CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China [2] College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, China.
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JL
Chen
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019175:DNA Methylation; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D000068877:Imatinib Mesylate; D019169:Jurkat Cells; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D062085:RNA, Long Noncoding / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D014183:Transplantation, Heterologous
D001549:Benzamides; C489427:MYC protein, human; D035683:MicroRNAs; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011743:Pyrimidines; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human