title: The SIRT1/TP53 axis is activated upon B-cell receptor triggering via miR-132 up-regulation in chronic lymphocytic leukemia cells.
abstract: The B-cell receptor (BCR) plays an important role in the pathogenesis and progression of chronic lymphocytic leukemia (CLL). By global microRNA profiling of CLL cells stimulated or not stimulated by anti-IgM, significant up-regulation of microRNAs from the miR-132~212 cluster was observed both in IGHV gene unmutated (UM) and mutated (M) CLL cells. Parallel gene expression profiling identified SIRT1, a deacetylase targeting several proteins including TP53, among the top-ranked miR-132 target genes down-regulated upon anti-IgM exposure. The direct regulation of SIRT1 expression by miR-132 was demonstrated using luciferase assays. The reduction of SIRT1 mRNA and protein (P = 0.001) upon anti-IgM stimulation was associated with an increase in TP53 acetylation (P = 0.007), and the parallel up-regulation of the TP53 target gene CDKN1A. Consistently, miR-132 transfections of CLL-like cells resulted in down-regulation of SIRT1 and an induction of a TP53-dependent apoptosis. Finally, in a series of 134 CLL samples, miR-132, when expressed above the median value, associated with prolonged time-to-first-treatment in patients with M CLL (HR = 0.41; P = 0.02). Collectively, the miR-132/SIRT1/TP53 axis was identified as a novel pathway triggered by BCR engagement that further increases the complexity of the interactions between tumor microenvironments and CLL cells.
authors.affiliation: Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano, Pordenone, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Dal Bo
authors.affiliation: Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano, Pordenone, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: D'Agaro
authors.affiliation: Molecular Hematology, International Centre for Genetic Engineering and Biotechnology, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Gobessi
authors.affiliation: Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano, Pordenone, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Zucchetto
authors.affiliation: Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano, Pordenone, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Dereani
authors.affiliation: Division of Hematology, Department of Clinical and Experimental Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.affiliation: Clinica Ematologica, Centro Trapianti e Terapie Cellulari "Carlo Melzi" DISM, Azienda Ospedaliera Universitaria S. Maria Misericordia, Udine, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Zaja
authors.affiliation: Department of Internal Medicine and Hematology, Maggiore General Hospital, University of Trieste, Trieste, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pozzato
authors.affiliation: Division of Hematology, Ferrarotto Hospital, Catania, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Raimondo
authors.affiliation: Division of Hematology, Department of Clinical and Experimental Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.affiliation: Department of Hematology, Catholic University Hospital A. Gemelli, Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Laurenti
authors.affiliation: Division of Hematology, S. Eugenio Hospital and University of Tor Vergata, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Del Poeta
authors.affiliation: Molecular Hematology, International Centre for Genetic Engineering and Biotechnology, Rome, Italy.
authors.forename: Dimitar G
authors.initials: DG
authors.lastname: Efremov
authors.affiliation: Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano, Pordenone, Italy.
authors.forename: Valter
authors.initials: V
authors.lastname: Gattei
authors.affiliation: Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano, Pordenone, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bomben
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000502:physiology; D016158:Genes, p53; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C547077:MIRN132 microRNA, human; D035683:MicroRNAs; D011947:Receptors, Antigen, B-Cell; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: BCR; CLL; miR-132