Abstract 3543: A long noncoding RNA plays a critical role in Bcr-Abl-mediated cellular transformation

Abstract

It is well documented that malignant transformation of myeloid and lymphoid cells by Bcr-Abl involves the dysregulation or mutation of a variety of protein-coding genes that are normally involved in regulating the proliferation and survival of hematopoietic cells. However, the functional relevance of long noncoding RNAs (lncRNAs) and their in vivo regulation during Bcr-Abl-mediated tumorigenesis remain unknown, although recent studies have shown that aberrant expression of lncRNAs is associated with various human cancers. 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 mice expressing lncRNA-BGL3 were generated. We found that transgenic 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 PTEN. Further experiments demonstrated that lncRNA-BGL3 functioned as a competitive endogenous RNA (ceRNA) 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. Citation Format: Guijie Guo, Qingzheng Kang, Qinghuang Chen, Ouyang Jing, Jilong Chen. A long noncoding RNA plays a critical role in Bcr-Abl-mediated cellular transformation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3543. doi:10.1158/1538-7445.AM2014-3543