Ataluren‐driven restoration of Shwachman‐Bodian‐Diamond syndrome protein function in Shwachman‐Diamond syndrome bone marrow cells

Shwachman‐Diamond syndrome (SDS) is a rare inherited recessive disease mainly caused by mutations in the Shwachman‐Bodian‐Diamond syndrome (SBDS) gene, which encodes for the homonymous protein SBDS, whose function still remains to be fully established. SDS affects several organs causing bone marrow...

Full description

Saved in:
Bibliographic Details
Published in:American journal of hematology Vol. 93; no. 4; pp. 527 - 536
Main Authors: Bezzerri, Valentino, Bardelli, Donatella, Morini, Jacopo, Vella, Antonio, Cesaro, Simone, Sorio, Claudio, Biondi, Andrea, Danesino, Cesare, Farruggia, Piero, Assael, Baroukh Maurice, D'amico, Giovanna, Cipolli, Marco
Format: Journal Article
Language:English
Published: United States Wiley Subscription Services, Inc 01.04.2018
Subjects:
Acute myeloid leukemia
Apoptosis
Apoptosis - drug effects
Bone marrow
Bone Marrow Cells - metabolism
Bone Marrow Diseases - metabolism
Bone Marrow Diseases - pathology
Cells, Cultured
Clinical trials
Codon, Nonsense - drug effects
Cognitive ability
Colony-Forming Units Assay
Exocrine Pancreatic Insufficiency - metabolism
Exocrine Pancreatic Insufficiency - pathology
Gene Expression Regulation - drug effects
Hematology
Hemopoiesis
Humans
Lipomatosis - metabolism
Lipomatosis - pathology
Lymphoblasts
Mesenchyme
Monocytes - cytology
Monocytes - drug effects
Mutation
Myelodysplastic syndrome
Myeloid leukemia
Osteoprogenitor cells
Oxadiazoles - pharmacology
Pancreas
Patients
Phosphorylation
Phosphorylation - drug effects
Protein Processing, Post-Translational - drug effects
Proteins
Proteins - genetics
Rapamycin
Stromal cells
TOR protein
TOR Serine-Threonine Kinases - metabolism
ISSN:0361-8609, 1096-8652, 1096-8652
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Shwachman‐Diamond syndrome (SDS) is a rare inherited recessive disease mainly caused by mutations in the Shwachman‐Bodian‐Diamond syndrome (SBDS) gene, which encodes for the homonymous protein SBDS, whose function still remains to be fully established. SDS affects several organs causing bone marrow failure, exocrine pancreatic insufficiency, skeletal malformations, and cognitive disorders. About 15% of SDS patients develop myelodysplastic syndrome (MDS) and are at higher risk of developing acute myeloid leukemia (AML). Deficiency in SBDS expression has been associated with increased apoptosis and lack of myeloid differentiation in bone marrow hematopoietic progenitors. Importantly, most SDS patients carry nonsense mutations in SBDS. Since ataluren is a well‐characterized small molecule inhibitor that can suppress nonsense mutations, here, we have assessed the efficacy of this drug in restoring SBDS expression in hematopoietic cells obtained from a cohort of SDS patients. Remarkably, we show that ataluren treatment readily restores SBDS protein expression in different cell types, particularly bone marrow stem cells. Furthermore, ataluren promotes myeloid differentiation in hematopoietic progenitors, reduces apoptotic rate in primary PBMCs, and brings mammalian target of rapamycin phosphorylation levels back to normal in both lymphoblasts and bone marrow mesenchymal stromal cells (BM‐MSCs). Since a specific therapy against SDS is currently lacking, these results provide the rationale for ataluren repurposing clinical trials.
Bibliography:Funding information
Valentino Bezzerri and Donatella Bardelli equally contributed to this study.
Giovanna D'amico and Marco Cipolli jointly supervised this work.
Associazione Italiana Sindrome di Shwachman, Grant/Award Number: AISS‐2017 to AV and MC
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
ISSN:0361-8609
1096-8652
1096-8652
DOI:10.1002/ajh.25025