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Sci Transl Med. 2019 Jul 10;11(500). pii: eaav5467. doi: 10.1126/scitranslmed.aav5467.

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

Bondu S1,2,3,4, Alary AS1,2,3,4,5, Lefèvre C1,2,3,4,6, Houy A7, Jung G8, Lefebvre T1,6,9, Rombaut D1,2,3,4, Boussaid I1,2,3,4, Bousta A1,2,3,4, Guillonneau F1,2,3,4,10, Perrier P11, Alsafadi S12, Wassef M13, Margueron R13, Rousseau A1,2,3,4, Droin N14, Cagnard N1,15, Kaltenbach S1,16, Winter S17, Kubasch AS18, Bouscary D1,2,3,4,19, Santini V20, Toma A21, Hunault M22, Stamatoullas A23, Gyan E24, Cluzeau T25, Platzbecker U18, Adès L1,26, Puy H1,6,9, Stern MH27, Karim Z1,6,9, Mayeux P1,2,3,4,6,10, Nemeth E8, Park S28, Ganz T8, Kautz L11, Kosmider O29,2,3,4,5,6, Fontenay M29,2,3,4,5,6.

Author information

Université de Paris, Paris 75006, France.
Institut Cochin, Département Développement, Reproduction, Cancer, Paris 75014, France.
Institut National de la Santé et de la Recherche médicale (INSERM) U1016, Paris 75014, France.
Centre National de la Recherche Scientifique (CNRS) Unité Mixte de recherche (UMR) 8104, Paris 75014, France.
Service d'hématologie biologique, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Paris Centre-Cochin, Paris 75014, France.
Laboratoire d'excellence du Globule Rouge GR-Ex, Paris 75015, France.
Institut Curie, PSL Research University, Human Genetics and Oncogenesis, Paris 75005, France.
Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
INSERM, UMR 1149/ERL CNRS 8252, Centre de Recherches sur l'inflammation, Université de Paris, Paris 75018, France.
Proteomic platform 3P5, Université de Paris, Paris 75014, France.
Institut de Recherche en Santé Digestive (IRSD), Université de Toulouse, INSERM U1220, Institut National de la Recherche Agronomique U1416, Ecole Nationale Vétérinaire de Toulouse, Université Paul Sabatier, Toulouse 31024, France.
Institut Curie, PSL Research University, Department of Translational Research, Paris 75005, France.
Institut Curie, PSL Research University, INSERM 934/UMR 3215, Genetics and biology of Development, Paris 75005 France.
Institut Gustave Roussy, Genomic platform, Villejuif 94805, France.
Platform Bioinformatics, Université de Paris, Paris 75015, France.
Laboratoire de Génétique, AP-HP, Hôpital Necker, Paris 75015, France.
Medical Clinic und Policlinic 1, Technische Universität Dresden, Dresden 01307, Germany.
Medical Clinic und Policlinic 1, Hematology and Cellular Therapy, University Hospital, Leipzig 04103, Germany.
Service d'Hématologie clinique, AP-HP, Hôpitaux Universitaires Paris Centre-Cochin, Paris 75014, France.
MDS unit, Hematology, AOU Careggi, University of Florence, Florence 50134, Italy.
Département d'Hématologie, AP-HP, Hôpital Henri-Mondor, Université Paris 12, Créteil 94000, France.
Service des Maladies du Sang, Centre hospitalo-universitaire, Angers 49100, France.
Département d'hématologie, Centre Henri-Becquerel, Rouen 76038, France.
Service d'hématologie et thérapie cellulaire, Centre hospitalo-universitaire, CNRS ERL 7001 LNOx, Université de Tours, Tours 37044, France.
Côte d'Azur University, CHU of Nice, Hematology department and INSERM U1065, Mediterranean Center of Molecular Medecine, Nice 06204, France.
Service d'Hématologie Senior, AP-HP, Hôpital Saint-Louis, Paris 75010, France.
Institut Curie, PSL Research University, INSERM U830, Genetics and biology of cancers, DNA repair and uveal melanoma (D.R.U.M.), Équipe labellisée par la Ligue nationale contre le cancer, Paris 75005, France.
Département d'Hématologie, Centre Hospitalier Universitaire, Université de Grenoble Alpes, La Tronche 38700, France.
Université de Paris, Paris 75006, France.


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 erythropoiesis 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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