Abstract
BackgroundDysregulation of long noncoding RNAs (lncRNAs) has been linked to various human cancers. Bcr-Abl oncogene that results from a reciprocal translocation between human chromosome 9 and 22, is associated with several hematological malignancies. However, the role of lncRNAs in Bcr-Abl-induced leukemia remains largely unexplored.MethodsLncRNA cDNA microarray was employed to identify key lncRNAs involved in Bcr-Abl-mediated cellular transformation. Abl-transformed cell survival and xenografted tumor growth in mice were evaluated to dissect the role of imatinib-upregulated lncRNA 1 (IUR1) in Abl-induced tumorigenesis. Primary bone marrow transformation and in vivo leukemia transplant using lncRNA-IUR1 knockout (KO) mice were further conducted to address the functional relevance of lncRNA-IUR1 in Abl-mediated leukemia. Transcriptome RNA-seq and Western blotting were performed to determine the mechanisms by which lncRNA-IUR1 regulates Bcr-Abl-induced tumorigenesis.ResultsWe identified lncRNA-IUR1 as a critical negative regulator of Bcr-Abl-induced tumorigenesis. LncRNA-IUR1 expressed in a very low level in Bcr-Abl-positive cells from chronic myeloid leukemia patients. Interestingly, it was significantly induced in Abl-positive leukemic cells treated by imatinib. Depletion of lncRNA-IUR1 promoted survival of Abl-transformed human leukemic cells in experiments in vitro and xenografted tumor growth in mice, whereas ectopic expression of lncRNA-IUR1 sensitized the cells to apoptosis and suppressed tumor growth. In concert, silencing murine lncRNA-IUR1 in Abl-transformed cells accelerated cell survival and the development of leukemia in mice. Furthermore, lncRNA-IUR1 deficient mice were generated, and we observed that knockout of murine lncRNA-IUR1 facilitated Bcr-Abl-mediated primary bone marrow transformation. Moreover, animal leukemia model revealed that lncRNA-IUR1 deficiency promoted Abl-transformed cell survival and development of leukemia in mice. Mechanistically, we demonstrated that lncRNA-IUR1 suppressed Bcr-Abl-induced tumorigenesis through negatively regulating STAT5-mediated GATA3 expression.ConclusionsThese findings unveil an inhibitory role of lncRNA-IUR1 in Abl-mediated cellular transformation, and provide new insights into molecular mechanisms underlying Abl-induced leukemogenesis.
Highlights
Dysregulation of long noncoding RNAs has been linked to various human cancers
LncRNA‐imatinib-upregulated lncRNA 1 (IUR1) is a novel lncRNA whose expression is low in Bcr‐Abl‐positive leukemic cells but highly induced by imatinib To identify key long noncoding RNAs involved in Bcr-Abl-mediated tumorigenesis, an lncRNA microarray was employed to analyze the expression of lncRNAs in Bcr-Abl–positive K562 cells treated with or without the Abl kinase inhibitor imatinib
Numerous (See figure on page.) Fig. 1 LncRNA-IUR1 is identified as a novel lncRNA that is induced by imatinib treatment in Bcr-Abl-positive leukemic cells
Summary
Dysregulation of long noncoding RNAs (lncRNAs) has been linked to various human cancers. The role of lncRNAs in Bcr-Abl-induced leukemia remains largely unexplored. V-Abl is the oncogene of Abelson murine leukemia virus, which contributes to the malignant transformation of mouse pre-B cells and lymphoid tumorigenesis in mice [3]. Owing to their constitutive tyrosine kinase activity, Abl oncoproteins (Bcr-Abl, v-Abl) activate a variety of signaling pathways associated with cell survival and proliferation, such as PI3K/ AKT (phosphatidylinositol 3-kinase/protein kinase B) and JAK/STAT (Janus kinase/signal transducer and activator of transcription), resulting in uncontrolled cell survival and proliferation, and the development of leukemia [4,5,6]. The biological significance and underlying mechanisms of various lncRNAs in the development of leukemia remain poorly characterized
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