mTOR and STAT3 Pathway Hyper-Activation is Associated with evated Interleukin-6 Levels in Patients with Shwachman-Diamond Syndrome: Further Evidence of Lymphoid Lineage Impairment

Cancers

Marco Cipolli¹  Valentino Bezzerri²  Marisole Allegri²  Benedetta Fabrizzi²  Martina Api²  Antonio Benedetti³  Elisabetta D’Aversa⁴  Monica Borgatti⁴  Giulia Breveglieri⁴  Claudio Sorio⁵  Seth J. Corey⁶  Antonella Poloni⁷  Elena Marinelli Busilacchi⁷  Chiara Bovo⁸  Gloria Bedini⁹  Giovanna D’Amico⁹  Alice Giacomazzi^1,10  Antonio Vella^1,10  Vincenzo Bronte^1,10  Tiziana Cestari^1,10 

[1] Cystic Fibrosis Center, Azienda Ospedaliera Universitaria Integrata, 37126 Verona, Italy;Cystic Fibrosis Center, Azienda Ospedaliero Universitaria Ospedali Riuniti, 60126 Ancona, Italy;Department of Gastroenterology and Hepatology, Università Politecnica delle Marche, 60126 Ancona, Italy;Department of Life Sciences and Biotechnology, University of Ferrara, 44100 Ferrara, Italy;Department of Medicine, University of Verona, 37134 Verona, Italy;Department of Pediatric Hematology/Oncology and Stem Cell Transplantation, Cleveland Clinic, Cleveland, OH 44195, USA;Hematology Clinic, Università Politecnica delle Marche -AOU Ospedali Riuniti, 60126 Ancona, Italy;Hospital Health Direction, Azienda Ospedaliera Universitaria Integrata, 37126 Verona, Italy;Immunology and Cell Therapy Unit, Tettamanti Research Center, University of Milano-Bicocca, 20900 Monza, Italy;Unit of Immunology, Azienda Ospedaliera Universitaria Integrata, 37134 Verona, Italy;

关键词: stat3;    mtor;    bone marrow failure syndromes;    lymphocytes;   

DOI  :  10.3390/cancers12030597

来源: DOAJ

【 摘 要 】

Shwachman–Diamond syndrome (SDS) is a rare inherited bone marrow failure syndrome, resulting in neutropenia and a risk of myeloid neoplasia. A mutation in a ribosome maturation factor accounts for almost all of the cases. Lymphoid involvement in SDS has not been well characterized. We recently reported that lymphocyte subpopulations are reduced in SDS patients. We have also shown that the mTOR-STAT3 pathway is hyper-activated in SDS myeloid cell populations. Here we show that mTOR-STAT3 signaling is markedly upregulated in the lymphoid compartment of SDS patients. Furthermore, our data reveal elevated IL-6 levels in cellular supernatants obtained from lymphoblasts, bone marrow mononuclear and mesenchymal stromal cells, and plasma samples obtained from a cohort of 10 patients. Of note, everolimus-mediated inhibition of mTOR signaling is associated with basal state of phosphorylated STAT3. Finally, inhibition of mTOR-STAT3 pathway activation leads to normalization of IL-6 expression in SDS cells. Altogether, our data strengthen the hypothesis that SDS affects both lymphoid and myeloid blood compartment and suggest everolimus as a potential therapeutic agent to reduce excessive mTOR-STAT3 activation in SDS.

【 授权许可】

Unknown