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mTOR and STAT3 Pathway Hyper-Activation is Associated with Elevated 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...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139896/ https://www.ncbi.nlm.nih.gov/pubmed/32150944 http://dx.doi.org/10.3390/cancers12030597 |
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author | Vella, Antonio D’Aversa, Elisabetta Api, Martina Breveglieri, Giulia Allegri, Marisole Giacomazzi, Alice Marinelli Busilacchi, Elena Fabrizzi, Benedetta Cestari, Tiziana Sorio, Claudio Bedini, Gloria D’Amico, Giovanna Bronte, Vincenzo Poloni, Antonella Benedetti, Antonio Bovo, Chiara Corey, Seth J. Borgatti, Monica Cipolli, Marco Bezzerri, Valentino |
author_facet | Vella, Antonio D’Aversa, Elisabetta Api, Martina Breveglieri, Giulia Allegri, Marisole Giacomazzi, Alice Marinelli Busilacchi, Elena Fabrizzi, Benedetta Cestari, Tiziana Sorio, Claudio Bedini, Gloria D’Amico, Giovanna Bronte, Vincenzo Poloni, Antonella Benedetti, Antonio Bovo, Chiara Corey, Seth J. Borgatti, Monica Cipolli, Marco Bezzerri, Valentino |
author_sort | Vella, Antonio |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-7139896 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-71398962020-04-13 mTOR and STAT3 Pathway Hyper-Activation is Associated with Elevated Interleukin-6 Levels in Patients with Shwachman-Diamond Syndrome: Further Evidence of Lymphoid Lineage Impairment Vella, Antonio D’Aversa, Elisabetta Api, Martina Breveglieri, Giulia Allegri, Marisole Giacomazzi, Alice Marinelli Busilacchi, Elena Fabrizzi, Benedetta Cestari, Tiziana Sorio, Claudio Bedini, Gloria D’Amico, Giovanna Bronte, Vincenzo Poloni, Antonella Benedetti, Antonio Bovo, Chiara Corey, Seth J. Borgatti, Monica Cipolli, Marco Bezzerri, Valentino Cancers (Basel) Article 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. MDPI 2020-03-05 /pmc/articles/PMC7139896/ /pubmed/32150944 http://dx.doi.org/10.3390/cancers12030597 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Vella, Antonio D’Aversa, Elisabetta Api, Martina Breveglieri, Giulia Allegri, Marisole Giacomazzi, Alice Marinelli Busilacchi, Elena Fabrizzi, Benedetta Cestari, Tiziana Sorio, Claudio Bedini, Gloria D’Amico, Giovanna Bronte, Vincenzo Poloni, Antonella Benedetti, Antonio Bovo, Chiara Corey, Seth J. Borgatti, Monica Cipolli, Marco Bezzerri, Valentino mTOR and STAT3 Pathway Hyper-Activation is Associated with Elevated Interleukin-6 Levels in Patients with Shwachman-Diamond Syndrome: Further Evidence of Lymphoid Lineage Impairment |
title | mTOR and STAT3 Pathway Hyper-Activation is Associated with Elevated 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 Elevated 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 Elevated 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 Elevated 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 Elevated 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 elevated interleukin-6 levels in patients with shwachman-diamond syndrome: further evidence of lymphoid lineage impairment |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139896/ https://www.ncbi.nlm.nih.gov/pubmed/32150944 http://dx.doi.org/10.3390/cancers12030597 |
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