title: Growth differentiation factor 15 production is necessary for normal erythroid differentiation and is increased in refractory anaemia with ring-sideroblasts.
abstract: The disturbed erythropoiesis in patients with refractory anaemia with ring-sideroblasts (RARS) is characterized by intramedullary apoptosis of erythroid precursors and increased iron accumulation in mitochondria. To gain insight into these pathophysiological mechanisms we compared the gene expression profile (GEP) of erythroid precursors from RARS patients to the GEP of normal erythroid precursors. Three hundred sixty four probe sets were up-, and 253 probe sets downregulated in RARS cells. Interestingly, Growth Differentiation factor 15 (GDF15), a cytokine from the TGFbeta family, was dramatically upregulated in all RARS patients. Measurement of GDF15 in the sera from twenty RARS patients confirmed this finding by showing significantly, 7.2-fold, increased protein levels (3254 +/- 1400 ng/ml vs. 451 +/- 87 ng/ml in normals). In vitro studies demonstrated erythroid-specific production of GDF15 and dependence on erythropoietin. Induction of apoptosis by arsenic trioxide, a drug which acts via reduction of the mitochondrial membrane potential, also stimulated GDF15 production. Downregulation of endogenous GDF15 production in erythoblasts by specific siRNA led to diminished erythroid differentiation. Taken together, our findings demonstrate a new role for GDF15 in normal erythropoiesis as well as in the ineffective erythropoiesis of RARS patients.
authors.affiliation: Division of Haematology, University Hospital Geneva, Geneva, Switzerland.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Ramirez
authors.forename: Olivier
authors.initials: O
authors.lastname: Schaad
authors.forename: Stephane
authors.initials: S
authors.lastname: Durual
authors.forename: Dominique
authors.initials: D
authors.lastname: Cossali
authors.forename: Mylène
authors.initials: M
authors.lastname: Docquier
authors.forename: Photis
authors.initials: P
authors.lastname: Beris
authors.forename: Patrick
authors.initials: P
authors.lastname: Descombes
authors.forename: Thomas
authors.initials: T
authors.lastname: Matthes
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000753:Anemia, Refractory / Q000378:metabolism*; D000756:Anemia, Sideroblastic / Q000378:metabolism*; D016022:Case-Control Studies; D002454:Cell Differentiation; D002469:Cell Separation / Q000379:methods; D015672:Erythroid Precursor Cells / Q000737:chemistry*; D004920:Erythropoiesis / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D055436:Growth Differentiation Factor 15 / Q000032:analysis* / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D055436:Growth Differentiation Factor 15