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.

Vincenzo Bronte,Seth J Corey ,Marisole Allegri,Tiziana Cestari,Chiara Bovo,Valentino Bezzerri,Claudio Sorio,Benedetta Fabrizzi,Giovanna D’Amico,Alice Giacomazzi,Antonio Vella,Marco Cipolli,Giulia Breveglieri,Antonella Poloni,Elisabetta D’Aversa,Monica Borgatti,Gloria Bedini,Antonio Benedetti,Martina Api,Elena Marinelli Busilacchi

doi:10.3390/cancers12030597

Abstract

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.

Highlights

Shwachman–Diamond syndrome (SDS) is one of the most common inherited bone marrow failure syndromes (IBMFS), occurring in almost 1 out of 75,000 live births [1]
We previously reported that rapamycin-dependent mammalian target of rapamycin (mTOR) inhibition leads to normal levels of phosphorylation of STAT3 in SDS
STAT3 transcript and protein expression are markedly increased in PBMC and lymphoblastoid cell lines (LCL) obtained from SDS patients, confirming the involvement of the STAT3 pathway in lymphoid lineages

Summary

Introduction

Shwachman–Diamond syndrome (SDS) is one of the most common inherited bone marrow failure syndromes (IBMFS), occurring in almost 1 out of 75,000 live births [1]. SDS results from biallelic mutations in the Shwachman–Bodian–Diamond syndrome gene (SBDS), which encode the SBDS protein. SBDS protein cooperates with its partner elongation factor-like GTPase 1 (EFL1) to catalyze the release of the ribosomal anti-association factor eIF6, facilitating the assembly of the functional 80S ribosome [2,3,4]. The IBMFS are cancer predisposition syndromes, in particular myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). MDS has an incidence ranging from 2–12 cases per 100,000 people, which increases as individuals age [5].

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Conclusion