Novel lncRNA-IUR suppresses Bcr-Abl-induced tumorigenesis through regulation of STAT5-CD71 pathway

• Published in: Molecular cancer Vol. 18; no. 1; pp. 84 - 15
• Main Authors: Wang, Xuefei, Yang, Jianling, Guo, Guijie, Feng, Riyue, Chen, Ke, Liao, Yuan, Zhang, Lianfeng, Sun, Liping, Huang, Shile, Chen, Ji-Long
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 08.04.2019; BioMed Central; BMC
• Subjects: Acute lymphoblastic leukemia; Acute lymphocytic leukemia; Adolescent; Adult; Animals; Antigens, CD - genetics; Antigens, CD - metabolism; Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis; Bcr-Abl; BCR-ABL protein; Bone marrow; Bone marrow transplantation; Bosutinib; Cancer; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cell cycle; Cell Line, Tumor; Cell survival; Cellular transformation; Child, Preschool; Chromosome 9; Dasatinib; DNA microarrays; Female; Fusion protein; Fusion Proteins, bcr-abl - genetics; Fusion Proteins, bcr-abl - metabolism; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Genetic engineering; Genetic transformation; Genomes; Humans; Imatinib; Imatinib Mesylate - pharmacology; Immunoprecipitation; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Leukemogenesis; LncRNA; Lymphatic leukemia; Lymphocytes; Lymphocytic leukemia; Male; Mice; Mice, Nude; Nilotinib; Novels; Oligoribonucleotides - genetics; Oligoribonucleotides - metabolism; Peripheral blood; Ponatinib; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Proteins; Receptors, Transferrin - genetics; Receptors, Transferrin - metabolism; Ribonucleic acid; RNA; RNA, Long Noncoding - agonists; RNA, Long Noncoding - antagonists & inhibitors; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal Transduction; Stat5 protein; STAT5 Transcription Factor - genetics; STAT5 Transcription Factor - metabolism; Systematic review; Targeted cancer therapy; Transformed cells; Transgenic animals; Transgenic mice; Tumor suppressor genes; Tumorigenesis; Tumors; Xenograft Model Antitumor Assays; Xenografts; Beijing China; United States > US; China; LncRNA; Bcr-Abl; Imatinib; Cellular transformation; Leukemia
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-019-1013-3

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. 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. 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. 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.