Research Papers:

MicroRNA signatures and Foxp3+ cell count correlate with relapse occurrence in follicular lymphoma

Giorgio Malpeli _, Stefano Barbi, Corinna Greco, Simonetta Zupo, Anna Bertolaso, Maria Teresa Scupoli, Mauro Krampera, Paul Takam Kamga, Carlo Maria Croce, Aldo Scarpa and Alberto Zamò

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Oncotarget. 2018; 9:19961-19979. https://doi.org/10.18632/oncotarget.24987

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Giorgio Malpeli1,2, Stefano Barbi2, Corinna Greco3, Simonetta Zupo4, Anna Bertolaso2, Maria Teresa Scupoli5, Mauro Krampera3, Paul Takam Kamga3, Carlo Maria Croce6, Aldo Scarpa2,7 and Alberto Zamò2,8

1Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Section of Surgery, University of Verona, Verona, Italy

2Department of Diagnostics and Public Health, University of Verona, Verona, Italy

3Department of Medicine, Section of Hematology, Stem Cell Research Laboratory, University of Verona, Italy

4Laboratory of Molecular Diagnostics, IRCCS-AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

5Department of Medicine, Section of Hematology, University of Verona, Verona, Italy

6Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

7Applied Research on Cancer-Network, ARC-NET, University of Verona, Verona, Italy

8Department of Oncology, University of Torino, Torino, Italy

Correspondence to:

Giorgio Malpeli, email: [email protected]

Keywords: follicular lymphoma; relapse; microRNAs; Foxp3; heterogeneity

Received: August 23, 2017     Accepted: January 30, 2018     Published: April 13, 2018


First line drug treatment of follicular lymphoma (FL) patients is followed by a highly variable disease-free time before relapse in about one third of patients. No molecular marker is able to predict efficiently the risk of relapse. We investigated the expression profile of microRNAs (miRNAs) by microarrays and of the tumor microenvironment by immunohistochemistry in 26 FLs and 12 reactive lymph nodes (rLN) as reference. Twenty-nine miRNAs were differentially expressed in FLs compared to rLNs and some of them discriminated grade 1 from 3a FLs. Both FLs and rLNs displayed molecular heterogeneity. FLs grouped into two clusters mostly driven by the tumor T-cell content. Among 21 drug-treated FL patients with an average follow-up of 13.5 years, eight cases relapsed. Twenty-six miRNAs discriminated between relapsed and non-relapsed FLs. Ten miRNAs also correlated with Foxp3+ cells number. Notably, Foxp3+ cells were significantly less in relapsed patients and lower Foxp3+ cell number associated with shorter time-to-relapse. Foxp3+ cells did not co-expressed follicular helper T-cell markers and were therefore classified as regulatory T cells rather than follicular regulatory T-cells. These findings introduce new knowledge about the relationship between miRNA alterations and infiltrating immune cells and show that Foxp3+ cells might be predictive of disease relapse.

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