Abstract
BackgroundLong noncoding RNAs (lncRNAs), defined as the transcripts longer than 200 nt without protein-coding capacity, have been found to be aberrantly expressed in diverse human diseases including cancer. A reciprocal translocation between chromosome 9 and 22 generates the chimeric Bcr-Abl oncogene, which is associated with several hematological malignancies. However, the functional relevance between aberrantly expressed lncRNAs and Bcr-Abl-mediated leukemia remains obscure.MethodsLncRNA cDNA microarray was used to identify novel lncRNAs involved in Bcr-Abl-mediated cellular transformation. To study the functional relevance of novel imatinib-upregulated lncRNA (IUR) family in Abl-induced tumorigenesis, Abl-transformed cell survival and xenografted tumor growth in mice was evaluated. Primary bone marrow transformation and in vivo leukemia transplant using lncRNA-IUR knockdown (KD) transgenic mice were further conducted to corroborate the role of lncRNA-IUR in Abl-induced tumorigenesis. Transcriptome RNA-seq, Western blot, RNA pull down and RNA Immunoprecipitation (RIP) were employed to determine the mechanisms by which lncRNA-IUR-5 regulates Bcr-Abl-mediated tumorigenesis.ResultsWe identified a conserved lncRNA-IUR family as a key negative regulator of Bcr-Abl-induced tumorigenesis. Increased expression of lncRNA-IUR was detected in both human and mouse Abl-transformed cells upon imatinib treatment. In contrast, reduced expression of lncRNA-IUR was observed in the peripheral blood lymphocytes derived from Bcr-Abl-positive acute lymphoblastic leukemia (ALL) patients compared to normal subjects. Knockdown of lncRNA-IUR remarkably promoted Abl-transformed leukemic cell survival and xenografted tumor growth in mice, whereas overexpression of lncRNA-IUR had opposite effects. Also, silencing murine lncRNA-IUR promoted Bcr-Abl-mediated primary bone marrow transformation and Abl-transformed leukemia cell survival in vivo. Besides, knockdown of murine lncRNA-IUR in transgenic mice provided a favorable microenvironment for development of Abl-mediated leukemia. Finally, we demonstrated that lncRNA-IUR-5 suppressed Bcr-Abl-mediated tumorigenesis by negatively regulating STAT5-mediated expression of CD71.ConclusionsThe results suggest that lncRNA-IUR may act as a critical tumor suppressor in Bcr-Abl-mediated tumorigenesis by suppressing the STAT5-CD71 pathway. This study provides new insights into functional involvement of lncRNAs in leukemogenesis.
Highlights
Long noncoding RNAs, defined as the transcripts longer than 200 nt without proteincoding capacity, have been found to be aberrantly expressed in diverse human diseases including cancer
Long noncoding RNAs (LncRNAs)-imatinib-upregulated Long noncoding RNAs (lncRNAs) (IUR) family is identified as novel lncRNAs in leukemic cells induced by imatinib treatment To identify novel lncRNAs involved in Bcr-Abl-mediated cellular transformation, an lncRNA cDNA microarray (Agilent) was used to comprehensively analyze the expression of lncRNAs in K562 cells in response to treatment with imatinib (Abl kinase inhibitor)
Using the Open Reading Frame (ORF) Finder, we found that the potential ORFs for each transcript of lncRNA-IUR family were totally shorter than 300 bp (Additional file 2: Figure S1F)
Summary
Long noncoding RNAs (lncRNAs), defined as the transcripts longer than 200 nt without proteincoding capacity, have been found to be aberrantly expressed in diverse human diseases including cancer. A reciprocal translocation between chromosome 9 and 22 generates the chimeric Bcr-Abl oncogene, which is associated with several hematological malignancies. The functional relevance between aberrantly expressed lncRNAs and Bcr-Abl-mediated leukemia remains obscure. Bcr-Abl oncogene is generated by a reciprocal translocation between chromosome 9 and 22 in human genome, giving Bcr-Abl protein with constitutive tyrosine kinase activity [1]. Owing to development of tyrosine kinase inhibitors (TKIs), especially the first-generation imatinib, over 90% of CML patients have been cured in recent years [1, 8, 9]. Imatinib can competitively bind the adenosine triphosphate (ATP) binding pocket of Bcr-Abl, and effectively inhibit its tyrosine kinase activity [8, 9]. Significant progress has been made in treatment of Bcr-Abl-positive hematological malignancies, the precise mechanisms underlying Abl-mediated leukemogenesis are not fully understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
