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

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.

PU.1-Regulated Long Noncoding RNA lnc-MC Controls Human Monocyte/Macrophage Differentiation through Interaction with MicroRNA 199a-5p

“…In the past few years, further publications on ceRNAs have extended ceRNA categories into pseudogenes, lncRNAs, circular RNAs (circRNAs), small noncoding RNAs, and even mRNAs (50). For the hematopoietic system, Guo et al reported that lncRNA-BGL3, which regulates Bcr-Abl-mediated chronic myeloid leukemia (CML), acts as a ceRNA to soak up miR-17, miR-20a, miR-20b, miR-93, miR106a, and miR-106b and alleviate their repression of PTEN (52). Here we demonstrated that lnc-MC could interact directly and physically with miR-199a-5p, functioning as a ceRNA to release ACVR1B expression.…”

Natural course and biology of CML

“…The general mechanism by which lncRNAs function is not yet fully understood, but lncRNA-BGL3 was reported to play an important role in BCR-ABL1 transformation. In K562 and primary CML cells, BCR-ABL1 inhibits the expression of this lncRNA in a kinase-dependent manner via the MYC transcription factor [87]. Forced expression of lncRNA-BGL3 in K562 cells induced apoptosis and reduced the ability of these cells to engraft in mice.…”

The Emerging Function and Mechanism of ceRNAs in Cancer

“…LncRNA-BGL3 exerted a tumor-suppressing function by serving as a PTEN ceRNA and its expression was repressed by Bcr-Abl through c-Myc-dependent DNA methylation [76]. …”