Ataluren improves myelopoiesis and neutrophil chemotaxis by restoring ribosome biogenesis and reducing p53 levels in Shwachman-Diamond syndrome cells.
Shwachman-Diamond syndrome
ataluren
inherited bone marrow failure syndromes
myelodysplastic syndromes
translational readthrough-inducing drugs
Journal
British journal of haematology
ISSN: 1365-2141
Titre abrégé: Br J Haematol
Pays: England
ID NLM: 0372544
Informations de publication
Date de publication:
24 Oct 2023
24 Oct 2023
Historique:
revised:
18
09
2023
received:
23
03
2023
accepted:
20
09
2023
medline:
25
10
2023
pubmed:
25
10
2023
entrez:
25
10
2023
Statut:
aheadofprint
Résumé
Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, exocrine pancreatic insufficiency and skeletal abnormalities. SDS bone marrow haematopoietic progenitors show increased apoptosis and impairment in granulocytic differentiation. Loss of Shwachman-Bodian-Diamond syndrome (SBDS) expression results in reduced eukaryotic 80S ribosome maturation. Biallelic mutations in the SBDS gene are found in ~90% of SDS patients, ~55% of whom carry the c.183-184TA>CT nonsense mutation. Several translational readthrough-inducing drugs aimed at suppressing nonsense mutations have been developed. One of these, ataluren, has received approval in Europe for the treatment of Duchenne muscular dystrophy. We previously showed that ataluren can restore full-length SBDS protein synthesis in SDS-derived bone marrow cells. Here, we extend our preclinical study to assess the functional restoration of SBDS capabilities in vitro and ex vivo. Ataluren improved 80S ribosome assembly and total protein synthesis in SDS-derived cells, restored myelopoiesis in myeloid progenitors, improved neutrophil chemotaxis in vitro and reduced neutrophil dysplastic markers ex vivo. Ataluren also restored full-length SBDS synthesis in primary osteoblasts, suggesting that its beneficial role may go beyond the myeloid compartment. Altogether, our results strengthened the rationale for a Phase I/II clinical trial of ataluren in SDS patients who harbour the nonsense mutation.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIH HHS
ID : R01 DK132812
Pays : United States
Informations de copyright
© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.
Références
Myers KC, Furutani E, Weller E, Siegele B, Galvin A, Arsenault V, et al. Clinical features and outcomes of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia: a multicentre, retrospective, cohort study. Lancet Haematol. 2020;7(3):e238-e246.
Dror Y, Freedman MH. Shwachman-Diamond syndrome: an inherited preleukemic bone marrow failure disorder with aberrant hematopoietic progenitors and faulty marrow microenvironment. Blood. 1999;94(9):3048-3054.
Bezzerri V, Vella A, Gennaro GD, Ortolani R, Nicolis E, Cesaro S, et al. Peripheral blood immunophenotyping in a large cohort of patients with Shwachman-Diamond syndrome. Pediatr Blood Cancer. 2019;66(5):e27597.
Donadieu J, Leblanc T, Bader Meunier B, Barkaoui M, Fenneteau O, Bertrand Y, et al. Analysis of risk factors for myelodysplasias, leukemias and death from infection among patients with congenital neutropenia. Experience of the French Severe Chronic Neutropenia Study Group. Haematologica. 2005;90(1):45-53.
Elghetany MT, Alter BP. p53 protein overexpression in bone marrow biopsies of patients with Shwachman-Diamond syndrome has a prevalence similar to that of patients with refractory anemia. Arch Pathol Lab Med. 2002;126(4):452-455.
Frattini A, Bolamperti S, Valli R, Cipolli M, Pinto RM, Bergami E, et al. Enhanced p53 levels are involved in the reduced mineralization capacity of osteoblasts derived from Shwachman-Diamond syndrome subjects. Int J Mol Sci. 2021;22(24):13331.
Boocock GR, Morrison JA, Popovic M, Richards N, Ellis L, Durie PR, et al. Mutations in SBDS are associated with Shwachman-Diamond syndrome. Nat Genet. 2003;33(1):97-101.
In K, Zaini MA, Müller C, Warren AJ, von Lindern M, Calkhoven CF. Shwachman-Bodian-Diamond syndrome (SBDS) protein deficiency impairs translation re-initiation from C/EBPα and C/EBPβ mRNAs. Nucleic Acids Res. 2016;44(9):4134-4146.
Finch AJ, Hilcenko C, Basse N, Drynan LF, Goyenechea B, Menne TF, et al. Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome. Genes Dev. 2011;25(9):917-929.
Morini J, Nacci L, Babini G, Cesaro S, Valli R, Ottolenghi A, et al. Whole exome sequencing discloses heterozygous variants in the DNAJC21 and EFL1 genes but not in SRP54 in 6 out of 16 patients with Shwachman-Diamond syndrome carrying biallelic SBDS mutations. Br J Haematol. 2018;185:627-630.
Bezzerri V, Cipolli M. Shwachman-Diamond syndrome: molecular mechanisms and current perspectives. Mol Diagn Ther. 2018;23:281-290.
Kurosaki T, Popp MW, Maquat LE. Quality and quantity control of gene expression by nonsense-mediated mRNA decay. Nat Rev Mol Cell Biol. 2019;20(7):406-420.
Goldmann T, Overlack N, Möller F, Belakhov V, van Wyk M, Baasov T, et al. A comparative evaluation of NB30, NB54 and PTC124 in translational read-through efficacy for treatment of an USH1C nonsense mutation. EMBO Mol Med. 2012;4(11):1186-1199.
Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature. 2007;447(7140):87-91.
Ryan NJ. Ataluren: first global approval. Drugs. 2014;74(14):1709-1714.
Huang S, Bhattacharya A, Ghelfi MD, Li H, Fritsch C, Chenoweth DM, et al. Ataluren binds to multiple protein synthesis apparatus sites and competitively inhibits release factor-dependent termination. Nat Commun. 2022;13(1):2413.
Ng MY, Li H, Ghelfi MD, Goldman YE, Cooperman BS. Ataluren and aminoglycosides stimulate read-through of nonsense codons by orthogonal mechanisms. Proc Natl Acad Sci U S A. 2021;118(2):e2020599118.
Bezzerri V, Bardelli D, Morini J, Vella A, Cesaro S, Sorio C, et al. Ataluren-driven restoration of Shwachman-Bodian-Diamond syndrome protein function in Shwachman-diamond syndrome bone marrow cells. Am J Hematol. 2018;93(4):527-536.
Robey PG, Termine JD. Human bone cells in vitro. Calcif Tissue Int. 1985;37(5):453-460.
Bezzerri V, Vella A, Calcaterra E, Finotti A, Gasparello J, Gambari R, et al. New insights into the Shwachman-Diamond Syndrome-related haematological disorder: hyper-activation of mTOR and STAT3 in leukocytes. Sci Rep. 2016;6:33165.
Galbiati A, Penzo M, Bacalini MG, Onofrillo C, Guerrieri AN, Garagnani P, et al. Epigenetic up-regulation of ribosome biogenesis and more aggressive phenotype triggered by the lack of the histone demethylase JHDM1B in mammary epithelial cells. Oncotarget. 2017;8(23):37091-37103.
De Vitis E, La Pesa V, Gervaso F, Romano A, Quattrini A, Gigli G, et al. A microfabricated multi-compartment device for neuron and Schwann cell differentiation. Sci Rep. 2021;11(1):7019.
Calamita P, Miluzio A, Russo A, Pesce E, Ricciardi S, Khanim F, et al. SBDS-deficient cells have an altered homeostatic equilibrium due to translational inefficiency which explains their reduced fitness and provides a logical framework for intervention. PLoS Genet. 2017;13(1):e1006552.
Warren AJ. Molecular basis of the human ribosomopathy Shwachman-Diamond syndrome. Adv Biol Regul. 2018;67:109-127.
Amar-Schwartz A, Cohen Y, Elhaj A, Ben-Hur V, Siegfried Z, Karni R, et al. Inhibition of nonsense-mediated mRNA decay may improve stop codon read-through therapy for Duchenne muscular dystrophy. Hum Mol Genet. 2023;32(15):2455-2463.
Savage SA, Dufour C. Classical inherited bone marrow failure syndromes with high risk for myelodysplastic syndrome and acute myelogenous leukemia. Semin Hematol. 2017;54(2):105-114.
Schmidt EK, Clavarino G, Ceppi M, Pierre P. SUnSET, a nonradioactive method to monitor protein synthesis. Nat Methods. 2009;6(4):275-277.
Van Lochem EG, Van Der Velden VHJ, Wind HK, Te Marvelde JG, Westerdaal NAC, Van Dongen JJM. Immunophenotypic differentiation patterns of normal hematopoiesis in human bone marrow: reference patterns for age-related changes and disease-induced shifts. Cytometry. 2004;60B(1):1-13.
Maynadié M, Picard F, Husson B, Chatelain B, Cornet Y, Le Roux G, et al. Immunophenotypic clustering of myelodysplastic syndromes. Blood. 2002;100(7):2349-2356.
Orelio C, Kuijpers TW. Shwachman-Diamond syndrome neutrophils have altered chemoattractant-induced F-Actin polymerization and polarization characteristics. Haematologica. 2009;94(3):409-413.
Stepanovic V, Wessels D, Goldman FD, Geiger J, Soll DR. The chemotaxis defect of Shwachman-Diamond syndrome leukocytes. Cell Motil Cytoskeleton. 2004;57(3):158-174.
Zhao W, Zhao H, Li M, Huang C. Microfluidic devices for neutrophil chemotaxis studies. J Transl Med. 2020;18(1):168.
Thada V, Miller JN, Kovács AD, Pearce DA. Tissue-specific variation in nonsense mutant transcript level and drug-induced read-through efficiency in the Cln1(R151X) mouse model of INCL. J Cell Mol Med. 2016;20(2):381-385.
Roy B, Friesen WJ, Tomizawa Y, Leszyk JD, Zhuo J, Johnson B, et al. Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression. Proc Natl Acad Sci U S A. 2016;113(44):12508-12513.
Chowdhury HM, Siddiqui MA, Kanneganti S, Sharmin N, Chowdhury MW, Nasim MT. Aminoglycoside-mediated promotion of translation readthrough occurs through a non-stochastic mechanism that competes with translation termination. Hum Mol Genet. 2018;27(2):373-384.
Finkel RS, Flanigan KM, Wong B, Bönnemann C, Sampson J, Sweeney HL, et al. Phase 2a study of ataluren-mediated dystrophin production in patients with nonsense mutation Duchenne muscular dystrophy. PLoS One. 2013;8(12):e81302.
Sermet-Gaudelus I, Boeck KD, Casimir GJ, Vermeulen F, Leal T, Mogenet A, et al. Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis. Am J Respir Crit Care Med. 2010;182(10):1262-1272.
Sen S, Wang H, Nghiem CL, Zhou K, Yau J, Tailor CS, et al. The ribosome-related protein, SBDS, is critical for normal erythropoiesis. Blood. 2011;118(24):6407-6417.
Yamaguchi M, Fujimura K, Toga H, Khwaja A, Okamura N, Chopra R. Shwachman-Diamond syndrome is not necessary for the terminal maturation of neutrophils but is important for maintaining viability of granulocyte precursors. Exp Hematol. 2007;35(4):579-586.
Zambetti NA, Ping Z, Chen S, Kenswil KJG, Mylona MA, Sanders MA, et al. Mesenchymal inflammation drives genotoxic stress in hematopoietic stem cells and predicts disease evolution in human pre-leukemia. Cell Stem Cell. 2016;19(5):613-627.
Zha J, Kunselman LK, Xie HM, Ennis B, Shah YB, Qin X, et al. Inducible Sbds deletion impairs bone marrow niche capacity to engraft donor bone marrow after transplantation. Blood Adv. 2022;6(1):108-120.