PMID- 30961617 OWN - NLM STAT- MEDLINE DCOM- 20190819 LR - 20200309 IS - 1476-4598 (Electronic) IS - 1476-4598 (Linking) VI - 18 IP - 1 DP - 2019 Apr 8 TI - Novel lncRNA-IUR suppresses Bcr-Abl-induced tumorigenesis through regulation of STAT5-CD71 pathway. PG - 84 LID - 10.1186/s12943-019-1013-3 [doi] LID - 84 AB - BACKGROUND: Long 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. METHODS: LncRNA 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. RESULTS: We 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. CONCLUSIONS: The 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. FAU - Wang, Xuefei AU - Wang X AD - CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, 100101, China. AD - University of Chinese Academy of Sciences, Beijing, China. FAU - Yang, Jianling AU - Yang J AD - Department of Immunology, Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Hebei Medical University, Shijiazhuang, China. FAU - Guo, Guijie AU - Guo G AD - CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, 100101, China. FAU - Feng, Riyue AU - Feng R AD - CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, 100101, China. AD - Institute of Physical Science and Information Technology, Anhui University, Hefei, 230601, China. FAU - Chen, Ke AU - Chen K AD - CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, 100101, China. FAU - Liao, Yuan AU - Liao Y AD - Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China. FAU - Zhang, Lianfeng AU - Zhang L AD - Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, Beijing, China. FAU - Sun, Liping AU - Sun L AD - Department of Blood Transfusion, Chinese PLA General Hospital, Beijing, China. FAU - Huang, Shile AU - Huang S AD - Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA. FAU - Chen, Ji-Long AU - Chen JL AD - Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China. chenjl@im.ac.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190408 PL - England TA - Mol Cancer JT - Molecular cancer JID - 101147698 RN - 0 (Antigens, CD) RN - 0 (Antineoplastic Agents) RN - 0 (CD71 antigen) RN - 0 (Oligoribonucleotides) RN - 0 (RNA, Long Noncoding) RN - 0 (RNA, Small Interfering) RN - 0 (Receptors, Transferrin) RN - 0 (STAT5 Transcription Factor) RN - 8A1O1M485B (Imatinib Mesylate) RN - EC 2.7.10.2 (Fusion Proteins, bcr-abl) MH - Adolescent MH - Adult MH - Animals MH - Antigens, CD/*genetics/metabolism MH - Antineoplastic Agents/pharmacology MH - Carcinogenesis/genetics/metabolism/pathology MH - Cell Line, Tumor MH - Child, Preschool MH - Female MH - Fusion Proteins, bcr-abl/*genetics/metabolism MH - *Gene Expression Regulation, Neoplastic MH - Humans MH - Imatinib Mesylate/pharmacology MH - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/*genetics/metabolism/pathology MH - Male MH - Mice MH - Mice, Nude MH - Oligoribonucleotides/genetics/metabolism MH - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/*genetics/metabolism/pathology MH - RNA, Long Noncoding/agonists/antagonists & inhibitors/*genetics/metabolism MH - RNA, Small Interfering/genetics/metabolism MH - Receptors, Transferrin/*genetics/metabolism MH - STAT5 Transcription Factor/*genetics/metabolism MH - Signal Transduction MH - Xenograft Model Antitumor Assays PMC - PMC6454664 OTO - NOTNLM OT - Bcr-Abl OT - Cellular transformation OT - Imatinib OT - Leukemia OT - LncRNA COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: The present study was approved by the Research Ethics Committee of Institute of Microbiology, Chinese Academy of Sciences. All participants signed informed consent prior to using the peripheral blood cells for scientific research. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2019/04/10 06:00 MHDA- 2019/08/20 06:00 PMCR- 2019/04/08 CRDT- 2019/04/10 06:00 PHST- 2019/01/12 00:00 [received] PHST- 2019/03/25 00:00 [accepted] PHST- 2019/04/10 06:00 [entrez] PHST- 2019/04/10 06:00 [pubmed] PHST- 2019/08/20 06:00 [medline] PHST- 2019/04/08 00:00 [pmc-release] AID - 10.1186/s12943-019-1013-3 [pii] AID - 1013 [pii] AID - 10.1186/s12943-019-1013-3 [doi] PST - epublish SO - Mol Cancer. 2019 Apr 8;18(1):84. doi: 10.1186/s12943-019-1013-3.