Molecular cancer, 2019-04, Vol.18 (1), p.84-84, Article 84
2019
Details
- Autor(en) / Beteiligte
- Titel
- Novel lncRNA-IUR suppresses Bcr-Abl-induced tumorigenesis through regulation of STAT5-CD71 pathway
- Ist Teil von
- Molecular cancer, 2019-04, Vol.18 (1), p.84-84, Article 84
- Ort / Verlag
- England: BioMed Central Ltd
- Erscheinungsjahr
- 2019
- Link zum Volltext
- Quelle
- SpringerLink (Online service)
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1476-4598eISSN: 1476-4598DOI: 10.1186/s12943-019-1013-3Titel-ID: cdi_doaj_primary_oai_doaj_org_article_9daa59af618844a2b330c7c3ff1ed1b9
- Format
- –
- Schlagworte
- Abl protein, Acute lymphoblastic leukemia, Acute lymphocytic leukemia, Adolescent, Adult, Animals, Antigens, CD - genetics, Antigens, CD - metabolism, Antineoplastic agents, Antineoplastic Agents - pharmacology, Apoptosis, BCR protein, Bcr-Abl, 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, Hematology, 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, Survival, Systematic review, Targeted cancer therapy, Transformed cells, Transgenic animals, Transgenic mice, Translocation, Tumor suppressor genes, Tumorigenesis, Tumors, Xenograft Model Antitumor Assays, Xenografts