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...

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Veröffentlicht in:Cancers 2020-03, Vol.12 (3), p.597
Hauptverfasser: 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
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container_issue 3
container_start_page 597
container_title Cancers
container_volume 12
creator 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
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.
doi_str_mv 10.3390/cancers12030597
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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
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