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 M. Wassef
(9)
,
Raphael Margueron
(9)
,
Alice Rousseau
(1)
,
Nathalie Droin
(10, 11)
,
Nicolas Cagnard
(12)
,
Sophie Kaltenbach
(13)
,
Susann Winter
(14)
,
Anne-Sophie Kubasch
(15)
,
Didier Bouscary
(2, 1)
,
Valeria Santini
(16)
,
Andrea Toma
(17)
,
Mathilde Hunault
(18)
,
Aspasia Stamatoullas
(19)
,
Emmanuel Gyan
(20)
,
Thomas Cluzeau
(21)
,
Uwe Platzbecker
(15)
,
Lionel Ades
(22)
,
Hervé Puy
(3, 6)
,
Marc-Henri Stern
(23)
,
Zoubida Karim
(3, 6)
,
Patrick Mayeux
(1, 3, 7)
,
Elizabeta Nemeth
(5)
,
Sophie Park
(24)
,
Tomas Ganz
(5)
,
Léon Kautz
(8)
,
Olivier Kosmider
(1, 3, 2)
,
Michaela Fontenay
(1, 3, 2)
1
IC UM3 (UMR 8104 / U1016) -
Institut Cochin
2 Hôpital Cochin [AP-HP]
3 Labex Gr-Ex - Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge
4 Institut Curie [Paris]
5 UCLA - University of California [Los Angeles]
6 CRI (UMR_S_1149 / ERL_8252 / U1149) - Centre de recherche sur l'Inflammation
7 3P5 - Plateforme protéomique 3P5 [Institut Cochin]
8 IRSD - Institut de Recherche en Santé Digestive
9 Génétique et Biologie du Développement
10 IGR - Institut Gustave Roussy
11 U1170 Inserm - Hématopoïèse normale et pathologique
12 Plateforme de bioinformatique [Université de Paris]
13 Service de Génétique Médicale [CHU Necker]
14 TU Dresden - Technische Universität Dresden = Dresden University of Technology
15 University Hospital Leipzig
16 UniFI - Università degli Studi di Firenze = University of Florence
17 Hôpital Henri Mondor
18 CHU Angers - Centre Hospitalier Universitaire d'Angers
19 CLCC Henri Becquerel - Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen
20 LNOx - ERL 7001 LNOx (Leukemic Niche & redOx metabolism / Niche leucémique et métabolisme redOx)
21 C3M - Centre méditerranéen de médecine moléculaire
22 Hôpital Saint-Louis
23 U830 - Unité de génétique et biologie des cancers
24 CHU - Centre Hospitalier Universitaire [Grenoble]
2 Hôpital Cochin [AP-HP]
3 Labex Gr-Ex - Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge
4 Institut Curie [Paris]
5 UCLA - University of California [Los Angeles]
6 CRI (UMR_S_1149 / ERL_8252 / U1149) - Centre de recherche sur l'Inflammation
7 3P5 - Plateforme protéomique 3P5 [Institut Cochin]
8 IRSD - Institut de Recherche en Santé Digestive
9 Génétique et Biologie du Développement
10 IGR - Institut Gustave Roussy
11 U1170 Inserm - Hématopoïèse normale et pathologique
12 Plateforme de bioinformatique [Université de Paris]
13 Service de Génétique Médicale [CHU Necker]
14 TU Dresden - Technische Universität Dresden = Dresden University of Technology
15 University Hospital Leipzig
16 UniFI - Università degli Studi di Firenze = University of Florence
17 Hôpital Henri Mondor
18 CHU Angers - Centre Hospitalier Universitaire d'Angers
19 CLCC Henri Becquerel - Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen
20 LNOx - ERL 7001 LNOx (Leukemic Niche & redOx metabolism / Niche leucémique et métabolisme redOx)
21 C3M - Centre méditerranéen de médecine moléculaire
22 Hôpital Saint-Louis
23 U830 - Unité de génétique et biologie des cancers
24 CHU - Centre Hospitalier Universitaire [Grenoble]
Thibaud Lefebvre
- Function : Author
- PersonId : 775696
- ORCID : 0000-0003-1398-6473
François Guillonneau
- Function : Author
- PersonId : 769176
- ORCID : 0000-0003-1484-4696
- IdRef : 060728477
Nathalie Droin
- Function : Author
- PersonId : 15266
- IdHAL : nathalie-droin
- ORCID : 0000-0002-9763-6317
- IdRef : 146768116
Mathilde Hunault
- Function : Author
- PersonId : 752203
- IdHAL : mathilde-hunault-berger
- ORCID : 0000-0001-7777-5216
Emmanuel Gyan
- Function : Author
- PersonId : 1131487
- ORCID : 0000-0002-7651-9189
Thomas Cluzeau
- Function : Author
- PersonId : 6292
- IdHAL : thomas-cluzeau
- IdRef : 082948860
Zoubida Karim
- Function : Author
- PersonId : 169884
- IdHAL : zoubida-karim
- ORCID : 0000-0002-3724-5592
- IdRef : 174709374
Elizabeta Nemeth
- Function : Author
- PersonId : 769333
- ORCID : 0000-0002-3477-2397
Olivier Kosmider
- Function : Author
- PersonId : 770386
- ORCID : 0000-0002-6021-4057
- IdRef : 114613753
Michaela Fontenay
- Function : Author
- PersonId : 770387
- ORCID : 0000-0002-5492-6349
- IdRef : 083817247
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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