Page 191 - Haematologica May 2020

Non-Hodgkin Lymphoma
Identification of a miR-146b-Fas ligand axis in the development of neutropenia in T large granular lymphocyte leukemia
Ferrata Storti Foundation
Haematologica 2020 Volume 105(5):1351-1360
Barbara Mariotti,1* Giulia Calabretto,2,3* Marzia Rossato,1§ Antonella Teramo,2,3 Monica Castellucci,1† Gregorio Barilà,2,3 Matteo Leoncin,2,3 Cristina Vicenzetto,2,3 Monica Facco,2,3 Gianpietro Semenzato,2,3 Flavia Bazzoni,1,* and Renato Zambello2,3,*
1Department of Medicine, Division of General Pathology, University of Verona, Verona; 2Department of Medicine, Hematology and Clinical Immunology section, University of Padua, Padua and 3Venetian Institute of Molecular Medicine (VIMM), Padua, Italy
§Present affiliation for MR is: Department of Biotechnology, University of Verona, Verona, Italy;
†Present affiliation for MC is: Genomics and transcriptomics platform, CPT, University of Verona, Verona, Italy
*BM, GC, FB and RZ contributed equally to this work.
ABSTRACT
T large granular lymphocyte leukemia (T-LGLL) is characterized by the expansion of several large granular lymphocyte clones, among which a subset of large granular lymphocytes showing constitutively activat-
ed STAT3, a specific CD8+/CD4– phenotype and the presence of neutropenia has been identified. Although STAT3 is an inducer of transcription of a large number of oncogenes, so far its relationship with miRNAs has not been eval- uated in T-LGLL patients. Here, we investigated whether STAT3 could carry out its pathogenetic role in T-LGLL through an altered expression of miRNAs. The expression level of 756 mature miRNA was assessed on puri- fied T large granular lymphocytes (T-LGLs) by using a TaqMan Human microRNA Array. Hierarchical Clustering Analysis of miRNA array data shows that the global miRNome clusters with CD8 T-LGLs. Remarkably, CD8 T-LGLs exhibit a selective and STAT3-dependent repression of miR- 146b expression, that significantly correlated with the absolute neutrophil counts and inversely correlated with the expression of Fas ligand (FasL), that is regarded as the most relevant factor in the pathogenesis of neutropenia. Experimental evidence demonstrates that the STAT3-dependent reduction of miR-146b expression in CD8 T-LGLs occurs as a consequence of miR- 146b promoter hypermethylation and results in the disruption of the HuR- mediated post-transcriptional machinery controlling FasL mRNA stabiliza- tion. Restoring miR-146b expression in CD8 T-LGLs lead to a reduction of HuR protein and, in turn, of FasL mRNA expression, thus providing mecha- nistic insights for the existence of a STAT3-miR146b-FasL axis and neutrope- nia in T-LGLL.
Introduction
T large granular lymphocytes leukemia (T-LGLL) is a rare disease characterized by the abnormal expansion of T large granular lymphocytes (T-LGLs) in the periph- eral blood.1,2 While the aetiology of the disease is still elusive, LGL proliferation is thought to be maintained through an impairment of the apoptotic machinery due to the activation of many survival signals.3 Among these, JAK/STAT signalling rep- resents one of the most important deregulated pathways in T-LGLL. In particular, leukemic LGLs are equipped with STAT3 constitutively over-expressed and in some cases over-activated.4,5 Moreover, in 30-40% of patients, STAT3 has been demonstrated to carry hot-spot mutations, likely resulting in STAT3 activation.6,7 This genetic lesion was also correlated by some authors with increased frequency of neutropenia5,7,8 which represents the most frequent cause of symptomatic dis-
Correspondence:
FLAVIA BAZZONI
flavia.bazzoni@univr.it
Received: May 3, 2019. Accepted: August 23, 2019. Pre-published: August 29, 2019.
doi:10.3324/haematol.2019.225060
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/5/1351
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