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A variant erythroferrone disrupts iron homeostasis in SF3B1-mutated myelodysplastic syndrome

Sabrina Bondu 1 Anne-Sophie Alary 1, 2 Carine Lefevre 1, 3 Alexandre Houy 4 Grace Jung 5 Thibaud Lefebvre 3, 6 David Rombaut 1 Ismael Boussaid 1 Abderrahmane Bousta 1 François Guillonneau 1, 7 Prunelle Perrier 8 Samar Alsafadi 4 Michel Wassef 9 Raphael Margueron 9 Alice Rousseau 1 Nathalie Droin 10 Nicolas Cagnard 11 Sophie Kaltenbach 12 Susann Winter 13 Anne-Sophie Kubasch 14 Didier Bouscary 2, 1 Valeria Santini 15 Andrea Toma 16 Mathilde Hunault 17 Aspasia Stamatoullas 18 Emmanuel Gyan 19 Thomas Cluzeau 20 Uwe Platzbecker 14 Lionel Ades 21 Hervé Puy 3, 6 Marc-Henri Stern 22 Zoubida Karim 3, 6 Patrick Mayeux 1, 3, 7 Elizabeta Nemeth 5 Sophie Park 23 Tomas Ganz 5 Léon Kautz 8 Olivier Kosmider 1, 3, 2 Michaela Fontenay 1, 3, 2
Abstract : Myelodysplastic syndromes (MDS) with ring sideroblasts are hematopoietic stem cell disorders with erythroid dysplasia and mutations in the SF3B1 splicing factor gene. Patients with MDS with SF3B1 mutations often accumulate excessive tissue iron, even in the absence of transfusions, but the mechanisms that are responsible for their parenchymal iron overload are unknown. Body iron content, tissue distribution, and the supply of iron for eryth-ropoiesis are controlled by the hormone hepcidin, which is regulated by erythroblasts through secretion of the erythroid hormone erythroferrone (ERFE). Here, we identified an alternative ERFE transcript in patients with MDS with the SF3B1 mutation. Induction of this ERFE transcript in primary SF3B1-mutated bone marrow erythroblasts generated a variant protein that maintained the capacity to suppress hepcidin transcription. Plasma concentrations of ERFE were higher in patients with MDS with an SF3B1 gene mutation than in patients with SF3B1 wild-type MDS. Thus, hepcidin suppression by a variant ERFE is likely responsible for the increased iron loading in patients with SF3B1-mutated MDS, suggesting that ERFE could be targeted to prevent iron-mediated toxicity. The expression of the variant ERFE transcript that was restricted to SF3B1-mutated erythroblasts decreased in lenalidomide-responsive anemic patients, identifying variant ERFE as a specific biomarker of clonal erythropoiesis.
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Sabrina Bondu, Anne-Sophie Alary, Carine Lefevre, Alexandre Houy, Grace Jung, et al.. A variant erythroferrone disrupts iron homeostasis in SF3B1-mutated myelodysplastic syndrome. Science Translational Medicine, American Association for the Advancement of Science, 2019, 11 (500), pp.eaav5467. ⟨10.1126/scitranslmed.aav5467⟩. ⟨inserm-02449216⟩

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