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

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

doi:10.18632/oncotarget.3905

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.

Highlights

Chronic lymphocytic leukemia (CLL) is a neoplastic disease characterized by highly variable clinical courses, ranging from rapid progression with fatal outcome to a relatively indolent behaviour with normal life expectancy [1]
A more aggressive clinical course has been associated with specific features of the B-cell receptor (BCR) expressed by chronic lymphocytic leukemia (CLL) cells, the so-called unmutated (UM) configuration, i.e. less www.impactjournals.com/oncotarget than 2% point mutations, of the genes coding for the immunoglobulin heavy-chain variable (IGHV) region of the BCR [1]
Results of Quantitative-real-time polymerase chain reactions (qRT-PCR) evaluations showed that constitutive miR-132 expression levels were variable, ranging from negligible values to values comparable to those found in CLL cells stimulated for 20 hours with anti-IgM

Summary

Introduction

Chronic lymphocytic leukemia (CLL) is a neoplastic disease characterized by highly variable clinical courses, ranging from rapid progression with fatal outcome to a relatively indolent behaviour with normal life expectancy [1]. The promising results of clinical trials with agents targeting the BCR signaling pathway, such as inhibitors of SYK, BTK, and PI3Kδ, again indicate that chronic BCR signaling is required for CLL cell growth and survival [9,10,11,12] It is worth noting, that CLL BCRs display features of auto-reactivity, their engagement potentially triggering signaling cascades leading to anergy and/or apoptosis, resulting in cell death rather than increased survival [13,14,15,16,17,18,19,20]. What outcome will predominate is determinate by several factors, such as BCR signal intensity, BCR signal duration, and availability of co-stimulatory signals [21,22,23]

Methods

Results

Conclusion