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    A new mechanism of systemic iron overload identified in a myelodysplastic syndrome

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    A study directed by Michaela Fontenay, published in Science Translational Medicine

    The team of Prof. Michaela Fontenay publishes the identification of a new mechanism of systemic iron overload in patients with SF3B1-mutated acquired sideroblastic anemia

     

    Myelodysplastic syndromes are clonal diseases of the hematopoietic stem cell. Acquired sideroblastic anemias are a particular subtype associated in more than 90% of cases with the presence of a heterozygous somatic mutation of the gene encoding the splice factor SF3B1. These anemias are characterized by a systemic accumulation of iron before any transfusion of red blood cells. Michaela Fontenay's team identified a splice variant of the ERFE / FAM132B gene encoding erythroferrone, whose expression is induced by the presence of a mutant SF3B1 gene in the bone marrow of patients. This variant transcript produced by erythroblasts is translated into a variant protein which has 4 additional amino acids and which suppresses, as the wild-type protein, the expression of hepcidin, an iron regulator peptide synthesized by the liver. This results in increased production of erythroferrone, increased suppression of hepcidin and iron overload as compared to myelodysplastic syndromes without mutation of the SF3B1 gene.

     

    The discovery, in recent years, of somatic mutations of splicing genes in cancers has led to an intensive search for transcript splicing abnormalities by global RNA sequencing, in order to identify the mechanisms of carcinogenesis. The goal is to establish a rationale for the use of splice-targeting pharmacological agents such as molecules interfering with the ability of the SF3b complex to interact with RNA or molecules degrading the RBM39 splice auxiliary factor. These molecules, some of which are in a phase 1 clinical trial, are not devoid of toxicity, suggesting to propose them only to patients whose prognosis is unfavorable.

    Mutations in the SF3B1 gene are restricted to certain cancers including acquired sideroblastic anemias. Patients with acquired sideroblastic anemia exhibit deep anemia, high transfusion requirements, and resistance to erythropoiesis stimulating agents such as erythropoietin and its bio-analogues. Their prognosis is favorable with a median survival of 9 years and a risk of transformation into acute leukemia of 15%, this risk being 30 to 40% in patients carrying another subtype of myelodysplastic syndrome and in particular in patients who have a mutation in another splice gene such as SRSF2 or U2AF1 or a TP53 gene mutation.

    In recent years, several teams have identified variant transcripts resulting from the presence of a mutation in the SF3B1 gene, but the relationship between the presence of these variants and the phenotype of the disease is unclear, in particular because the aberrant splicing results most often in the generation of transcripts with a premature stop codon that are degraded by non-sense mediated decay.

    The authors, in collaboration with the team of Dr. MH Stern of the Institut Curie (INSERM U830), have identified from RNA-sequencing data of bone marrow cells of patients with SF3B1-mutated sideroblastic anemia, a variant transcript of the ERFE / FAM1323B gene among the transcripts whose overall expression is increased. This transcript is detected only in the context of the mutation of the SF3B1 gene, either after transfection of the gene coding for the mutant SF3B1K700E, or in primary cells from the marrow of patients. It is translated into a variant protein that has been identified in the primary erythroblasts of patients by the team of the proteomics platform 3P5 (Paris Descartes University).

    Hepcidin, described by Dr. S Vaulont's team at the Institut Cochin, is a peptide hormone produced by the liver that is the main regulator of iron homeostasis in mammals, allowing the adaptation of Iron circulating as needed by regulating the import of iron into the duodenum and the recycling of iron by macrophages. Erythroferrone has been described for the first time as the major erythroid regulator of hepcidin in T Ganz's team (University of California, Los Angeles) by Léon Kautz.

    In collaboration with Léon Kautz (IRSD, INSERM U1220, Toulouse), the team has shown that the recombinant variant protein is multimeric like the wild-type protein and represses the transcription of hepcidin in cells of hepatocarcinoma lineages. Erythroferrone was assayed by ELISA in the plasma of patients included in several cohorts constituted by the biological hematology department of Cochin Hospital as part of a clinical research hospital program, by clinical trials of the Group Francophone Myelodysplasia or in the framework of international collaborations with the team of T Ganz. A high level of erythroferrone is predictive of iron overload and the presence of the variant transcript is a biomarker of clonal erythropoiesis. 

    In conclusion, this study, supported by the labEx GR-Ex and the Francophone Group of Myelodysplasia, identified for the first time a protein variant induced by the presence of a mutation of the splice gene SF3B1 in erythroblasts. This variant contributes to the elevation of plasma levels of erythroferrone and the repression of hepcidin, thus contributing to systemic iron overload, a major phenotypic characteristic of patients with SF3B1-mutated acquired sideroblastic anemia, and in this it represents a therapeutic target.

     

    Reference

    A variant erythroferrone disrupts iron homeostasis in SF3B1-mutated myelodysplastic syndrome.Sabrina Bondu,† Anne-Sophie Alary,† Carine Lefèvre, Alexandre Houy, Grace Jung, Thibaud Lefebvre, David Rombaut, Ismael Boussaid, Abderrahmane Bousta, François Guillonneau, Prunelle Perrier, Samar Alsafadi, Michel Wassef, Raphaël Margueron, Alice Rousseau, Nathalie Droin, Nicolas Cagnard, Sophie Kaltenbach, Susann Winter, Anne-Sophie Kubasch, Didier Bouscary, Valeria Santini, Andrea Toma, Mathilde Hunault, Aspasia Stamatoullas, Emmanuel Gyan, Thomas Cluzeau, Uwe Platzbecker, Lionel Adès, Hervé Puy, Marc-Henri Stern, Zoubida Karim, Patrick Mayeux, Elizabeta Nemeth, Sophie Park, Tomas Ganz, Léon Kautz, Olivier Kosmider,* Michaëla Fontenay*. Science Translational Medicine.

    † Equal contribution

    * Co-authors

     

    Patent

    New variants of erythroferrone and their use.  Michaela Fontenay, Olivier Kosmider, Léon Kautz, François Guillonneau, Carine Lefèvre, Marc-Henri Stern, Alexandre Houy, Samar Alsafadi

    Number: EP19305047.3. Date: January 16, 2019

     

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