The SIRT1/TP53 axis is activated upon B-cell receptor triggering via miR-132 up-regulation in chronic lymphocytic leukemia cells
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Michele Dal Bo1,*, Tiziana D’Agaro1,*, Stefania Gobessi2, Antonella Zucchetto1, Sara Dereani1, Davide Rossi3, Francesco Zaja4, Gabriele Pozzato5, Francesco Di Raimondo6, Gianluca Gaidano3, Luca Laurenti7, Giovanni Del Poeta8, Dimitar G. Efremov2, Valter Gattei1,#, Riccardo Bomben1,#
1Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy
2Molecular Hematology, International Centre for Genetic Engineering and Biotechnology, Rome, Italy
3Division of Hematology, Department of Clinical and Experimental Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
4Clinica Ematologica, Centro Trapianti e Terapie Cellulari "Carlo Melzi" DISM, Azienda Ospedaliera Universitaria S. Maria Misericordia, Udine, Italy
5Department of Internal Medicine and Hematology, Maggiore General Hospital, University of Trieste, Trieste, Italy
6Division of Hematology, Ferrarotto Hospital, Catania, Italy
7Department of Hematology, Catholic University Hospital A. Gemelli, Rome, Italy
8Division of Hematology, S.Eugenio Hospital and University of Tor Vergata, Rome, Italy
*These authors have equally contributed to this study as first authors
#These authors have equally contributed to this study as senior authors
Riccardo Bomben, e-mail: [email protected]
Valter Gattei, e-mail: [email protected]
Keywords: CLL, BCR, miR-132
Received: February 23, 2015 Accepted: April 28, 2015 Published: May 11, 2015
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.
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