Deregulation of miRNAs-cMYC circuits is a key event in refractory celiac disease type-2 lymphomagenesis

Valentina Vaira, Gabriella Gaudioso, Maria Antonella Laginestra, Andrea Terrasi, Claudio Agostinelli, Silvano Bosari, Antonio Di Sabatino, Alessandro Vanoli, Marco Paulli, Stefano Ferrero, Leda Roncoroni, Vincenza Lombardo, Liyanage P. Perera, Sonia Fabris, Maurizio Vecchi, Stefano Pileri, Luca Elli

Research output: Contribution to journalArticle

Abstract

A percentage of celiac disease (CD) patients develop refractory type-2 disease (RCD2), a condition associated with increased risk of enteropathy-associated T-cell-lymphoma (EATL) and without therapeutic option. Therefore, we profiled the miRNome in series of peripheral T-cell lymphomas (PTCLs), CD, RCD1 or 2 and in the murine interleukin-15 (IL15)-transgenic (TG) model of RCD. The transcriptome was analyzed in 18 intestinal T-cell lymphomas (ITLs). Bioinformatics pipelines provided significant microRNA (miRNA) lists and predicted targets that were confirmed in a second set of patients. Our data show that ITLs have a unique miRNA profile with respect to other PTCLs. The c-MYC regulated miR-17/92 cluster distinguishes monomorphic epitheliotropic ITL (MEITL) from EATL and prognosticates EATL outcome. These miRNAs are decreased in IL15-TG mice upon Janus kinase (JAK) inhibition. The random forest algorithm identified a signature of 38 classifier miRNAs, among which, the miR-200 and miR-192/215 families were progressively lost in RCD2 and ITL-CD, whereas miR-17/92 and C19MC miRNAs were up-regulated. Accordingly, SMAD3, MDM2, c-Myc and activated-STAT3 were increased in RCD2 and EATL tissues while JAK inhibition in IL15-TG mice restored their levels to baseline. Our data suggest that miRNAs circuit supports activation of STAT3 and c-Myc oncogenic signaling in RCD2, thus contributing to lymphomagenesis. This novel understanding might pave the way to personalized medicine approaches for RCD and EATL.

Original languageEnglish
Pages (from-to)1151-1166
Number of pages16
JournalClinical science (London, England : 1979)
Volume134
Issue number10
DOIs
Publication statusPublished - May 29 2020

Keywords

  • celiac disease
  • EATL
  • miR-17/92
  • Myc
  • RCD type 2

ASJC Scopus subject areas

  • Medicine(all)

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