title: IL-4 Up-Regulates MiR-21 and the MiRNAs Hosted in the CLCN5 Gene in Chronic Lymphocytic Leukemia.
abstract: Interleukin 4 (IL-4) induces B-cell differentiation and survival of chronic lymphocytic leukemia (CLL) cells. MicroRNAs (miRNAs) regulate mRNA and protein expression, and several miRNAs, deregulated in CLL, might play roles as oncogenes or tumor suppressors. We have studied the miRNA profile of CLL, and its response to IL-4, by oligonucleotide microarrays, resulting in the detection of a set of 129 mature miRNAs consistently expressed in CLL, which included 41 differentially expressed compared to normal B cells (NBC), and 6 significantly underexpressed in ZAP-70 positive patients. IL-4 stimulation brought about up-regulation of the 5p and 3p mature variants of the miR-21 gene, which maps immediately downstream to the VMP1 gene, and of the mature forms generated from the miR-362 (3p and 5p), miR-500a (3p), miR-502 (3p), and miR-532 (3p and 5p) genes, which map within the third intron of the CLCN5 gene. Both genes are in turn regulated by IL-4, suggesting that these miRNAs were regulated by IL-4 as passengers from their carrier genes. Their levels of up-regulation by IL-4 significantly correlated with cytoprotection. MiR-21 has been reported to be leukemogenic, associated to bad prognosis in CLL, and the miRNA more frequently overexpressed in human cancer. Up-regulation by IL-4 of miR-21 and the miRNAs hosted in the CLCN5 locus may contribute to evasion of apoptosis of CLL cells. These findings indicate that the IL-4 pathway and the miRNAs induced by IL-4 are promising targets for the development of novel therapies in CLL.
authors.affiliation: Servicio de Inmunología, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Ruiz-Lafuente
authors.affiliation: Servicio de Inmunología, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: María-José
authors.initials: MJ
authors.lastname: Alcaraz-García
authors.affiliation: Servicio de Inmunología, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Sebastián-Ruiz
authors.affiliation: Servicio de Inmunología, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Universidad de Murcia, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Azahara-María
authors.initials: AM
authors.lastname: García-Serna
authors.affiliation: Servicio de Hematología y Hemoterapia, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Gómez-Espuch
authors.affiliation: Servicio de Hematología y Hemoterapia, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Universidad de Murcia, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: José-María
authors.initials: JM
authors.lastname: Moraleda
authors.affiliation: Servicio de Inmunología, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Minguela
authors.affiliation: Servicio de Inmunología, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Ana-María
authors.initials: AM
authors.lastname: García-Alonso
authors.affiliation: Servicio de Inmunología, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Parrado
mesh_terms: D017209:Apoptosis / Q000235:genetics; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D018118:Chloride Channels / Q000235:genetics* / Q000378:metabolism; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism* / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D034622:RNA Interference; D015203:Reproducibility of Results; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: C097503:CLC-5 chloride channel; D018118:Chloride Channels; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D015847:Interleukin-4