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
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 repor...
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doaj-aa7d154795f74440a1d870af5f4d14e12020-11-25T02:27:27ZengMDPI AGCancers2072-66942020-03-0112359710.3390/cancers12030597cancers12030597mTOR and STAT3 Pathway Hyper-Activation is Associated with evated Interleukin-6 Levels in Patients with Shwachman-Diamond Syndrome: Further Evidence of Lymphoid Lineage ImpairmentAntonio Vella0Elisabetta D’Aversa1Martina Api2Giulia Breveglieri3Marisole Allegri4Alice Giacomazzi5Elena Marinelli Busilacchi6Benedetta Fabrizzi7Tiziana Cestari8Claudio Sorio9Gloria Bedini10Giovanna D’Amico11Vincenzo Bronte12Antonella Poloni13Antonio Benedetti14Chiara Bovo15Seth J. Corey16Monica Borgatti17Marco Cipolli18Valentino Bezzerri19Unit of Immunology, Azienda Ospedaliera Universitaria Integrata, 37134 Verona, ItalyDepartment of Life Sciences and Biotechnology, University of Ferrara, 44100 Ferrara, ItalyCystic Fibrosis Center, Azienda Ospedaliero Universitaria Ospedali Riuniti, 60126 Ancona, ItalyDepartment of Life Sciences and Biotechnology, University of Ferrara, 44100 Ferrara, ItalyCystic Fibrosis Center, Azienda Ospedaliero Universitaria Ospedali Riuniti, 60126 Ancona, ItalyUnit of Immunology, Azienda Ospedaliera Universitaria Integrata, 37134 Verona, ItalyHematology Clinic, Università Politecnica delle Marche -AOU Ospedali Riuniti, 60126 Ancona, ItalyCystic Fibrosis Center, Azienda Ospedaliero Universitaria Ospedali Riuniti, 60126 Ancona, ItalyUnit of Immunology, Azienda Ospedaliera Universitaria Integrata, 37134 Verona, ItalyDepartment of Medicine, University of Verona, 37134 Verona, ItalyImmunology and Cell Therapy Unit, Tettamanti Research Center, University of Milano-Bicocca, 20900 Monza, ItalyImmunology and Cell Therapy Unit, Tettamanti Research Center, University of Milano-Bicocca, 20900 Monza, ItalyUnit of Immunology, Azienda Ospedaliera Universitaria Integrata, 37134 Verona, ItalyHematology Clinic, Università Politecnica delle Marche -AOU Ospedali Riuniti, 60126 Ancona, ItalyDepartment of Gastroenterology and Hepatology, Università Politecnica delle Marche, 60126 Ancona, ItalyHospital Health Direction, Azienda Ospedaliera Universitaria Integrata, 37126 Verona, ItalyDepartment of Pediatric Hematology/Oncology and Stem Cell Transplantation, Cleveland Clinic, Cleveland, OH 44195, USADepartment of Life Sciences and Biotechnology, University of Ferrara, 44100 Ferrara, ItalyCystic Fibrosis Center, Azienda Ospedaliera Universitaria Integrata, 37126 Verona, ItalyCystic Fibrosis Center, Azienda Ospedaliero Universitaria Ospedali Riuniti, 60126 Ancona, ItalyShwachman–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.https://www.mdpi.com/2072-6694/12/3/597stat3mtorbone marrow failure syndromeslymphocytes |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Antonio Vella Elisabetta D’Aversa Martina Api Giulia Breveglieri Marisole Allegri Alice Giacomazzi Elena Marinelli Busilacchi Benedetta Fabrizzi Tiziana Cestari Claudio Sorio Gloria Bedini Giovanna D’Amico Vincenzo Bronte Antonella Poloni Antonio Benedetti Chiara Bovo Seth J. Corey Monica Borgatti Marco Cipolli Valentino Bezzerri |
spellingShingle |
Antonio Vella Elisabetta D’Aversa Martina Api Giulia Breveglieri Marisole Allegri Alice Giacomazzi Elena Marinelli Busilacchi Benedetta Fabrizzi Tiziana Cestari Claudio Sorio Gloria Bedini Giovanna D’Amico Vincenzo Bronte Antonella Poloni Antonio Benedetti Chiara Bovo Seth J. Corey Monica Borgatti Marco Cipolli Valentino Bezzerri 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 stat3 mtor bone marrow failure syndromes lymphocytes |
author_facet |
Antonio Vella Elisabetta D’Aversa Martina Api Giulia Breveglieri Marisole Allegri Alice Giacomazzi Elena Marinelli Busilacchi Benedetta Fabrizzi Tiziana Cestari Claudio Sorio Gloria Bedini Giovanna D’Amico Vincenzo Bronte Antonella Poloni Antonio Benedetti Chiara Bovo Seth J. Corey Monica Borgatti Marco Cipolli Valentino Bezzerri |
author_sort |
Antonio Vella |
title |
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 |
title_short |
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 |
title_full |
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 |
title_fullStr |
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 |
title_full_unstemmed |
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 |
title_sort |
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 |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2020-03-01 |
description |
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. |
topic |
stat3 mtor bone marrow failure syndromes lymphocytes |
url |
https://www.mdpi.com/2072-6694/12/3/597 |
work_keys_str_mv |
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