Abstract LB037: Identification of imatinib-induced long noncoding RNAs involved in suppression of tumor growth mediated by bcr-abl oncogene

Abstract

Abstract Chronic myeloid leukemia (CML) is a hematological malignancy mainly caused by the Bcr-Abl oncogene that results from the reciprocal translocation between human chromosome 9 and 22, and occurs in more than 90% of CML cases. Bcr-Abl oncogene is also involved in tumorigenesis of other leukemia such as acute lymphoid leukemia (ALL). Although progress has been made in the understanding of signal transduction in Abl-mediated transformation, the molecular mechanisms underlying Abl-induced tumorigenesis are still not fully understood. It is well known that imatinib treatment can greatly suppress Bcr-Abl-mediated development of leukemia, but intracellular molecules induced by imatinib and their roles in the tumorigenesis remain largely to be determined. On the other hand, the majority of human transcripts lack protein-coding capacity, which are defined as noncoding RNAs (ncRNAs). Long noncoding RNAs (lncRNAs) play important roles in various vital biological processes. Notably, increasing number of lncRNAs have been linked to human diseases, including cancers. However, the role of lncRNAs in Bcr-Abl-induced leukemia remains largely unexplored. Here, we identified several imatinib-induced lncRNAs as critical regulator of Bcr-Abl-induced tumorigenesis. Most of these lncRNAs expressed in a very low levels in Bcr-Abl-positive cells from chronic myeloid leukemia patients. Interestingly, they could be significantly induced in Abl-positive leukemic cells treated by imatinib. Silencing these lncRNAs promoted survival of Abl-transformed human leukemic cells in experiments in vitro and xenografted tumor growth in mice, whereas ectopic expression of particular lncRNAs sensitized the cells to apoptosis and suppressed tumor growth. In concert, knockout of some murine lncRNAs in Abl-transformed cells accelerated cell survival and the development of leukemia in mice. Furthermore, some lncRNA deficient mice were generated, and we observed that knockout of particular murine lncRNAs facilitated Bcr-Abl-mediated primary bone marrow transformation. Moreover, animal leukemia model revealed that lncRNA deficiency promoted Abl-transformed cell survival and development of leukemia in mice. In summary, these findings unveil an inhibitory role of several critical lncRNAs in Abl-mediated cellular transformation, and provide new insights into molecular mechanisms underlying Abl-induced leukemogenesis. Citation Format: Jilong Chen, Yun Ma. Identification of imatinib-induced long noncoding RNAs involved in suppression of tumor growth mediated by bcr-abl oncogene [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB037.