Abstract 2454: Identification of a novel lncRNA family that is required for efficient cellular transformation by Bcr-Abl oncogene

Abstract

Abstract Human genome transcribes abundant long noncoding RNAs (lncRNAs) that are defined as the transcripts longer than 200 nt without protein-coding capacity. Recently, lncRNAs are being continuously recognized as critical regulators for various biological processes. Aberrant expression of lncRNAs has been shown to be a cornerstone in diverse human diseases and cancer development. Chronic myeloid leukemia (CML) is a hematological malignancy associated with a reciprocal translocation between chromosome 9 and 22 that generates the chimeric Bcr-Abl oncogene. About 10% of acute lymphoblastic leukemia (ALL) patients also contain Bcr-Abl oncogene. However, the functional relevance of lncRNAs in Bcr-Abl-mediated leukemia remains obscure. In this study, we perform a comprehensive analysis of lncRNAs in Bcr-Abl-positive K562 cells using a microarray of cDNAs encoding lncRNAs. This analysis revealed 987 upregulated lncRNAs and 1479 downregulated lncRNAs in response to treatment with imatinib, a Bcr-Abl inhibitor. Importantly, we identified a conserved, imatinib-inducible lncRNA (IIR) family, named lncRNA-IIR37. Upregulation of lncRNA-IIR37 has been detected in both human and mouse Abl-transformed cell lines after imatinib treatment. Interestingly, lncRNA-IIR37 levels are significantly lower in leukemic cells derived from Bcr-Abl-positive ALL patients than those in normal control group. Furthermore, altering lncRNA-IIR37 expression remarkably affects survival of Abl-transformed leukemic cells, and tumorigensis induced by leukemic cells in xenograft mouse model. Knockdown of lncRNA-IIR37 in transgenic mice significantly promotes Bcr-Abl-mediated primary bone marrow transformation. These results indicate that lncRNA-IIR37 functions as a suppressor gene in Bcr-Abl-induced tumorigenesis. In addition, we demonstrated that lncRNA-IIR37 directly bound and affected the phosphorylation of STAT5 to regulate leukemic cell survival. Together, our observations suggest that lncRNA-IIR37 is critically involved in Bcr-Abl-mediated leukemogenesis. These results provide novel insights into complicated mechanisms underlying cellular transformation by Bcr-Abl oncogene. Citation Format: Jilong Chen, Xuefei Wang. Identification of a novel lncRNA family that is required for efficient cellular transformation by Bcr-Abl oncogene [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2454.