The SIRT1/TP53 axis is activated upon B-cell receptor triggering via miR-132 up-regulation in chronic lymphocytic leukemia cells

Michele Dal Bo, Tiziana D'Agaro, Stefania Gobessi, Antonella Zucchetto, Sara Dereani, Davide Rossi, Francesco Zaja, Gabriele Pozzato, Francesco Di Raimondo, Gianluca Gaidano, Luca Laurenti, Giovanni Del Poeta, Dimitar G. Efremov, Valter Gattei, Riccardo Bomben

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)19102-19117
Number of pages16
JournalOncotarget
Volume6
Issue number22
Publication statusPublished - 2015

Keywords

  • BCR
  • CLL
  • miR-132

ASJC Scopus subject areas

  • Oncology

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