title: APG101 efficiently rescues erythropoiesis in lower risk myelodysplastic syndromes with severe impairment of hematopoiesis.
abstract: CD95, a member of the death receptor family initiates a caspase-dependent apoptosis, when activated by its ligand CD95L, thought to negatively regulate erythrocyte production in the bone marrow. We have previously shown that CD95 is overexpressed in two thirds of patients with a lower risk myelodysplastic syndrome (MDS) and that resistance to erythropoiesis-stimulating agents (ESA) is linked to poor residual erythropoiesis. In the present study, we show that CD95 overexpression and previous transfusion are independent predictive factors of ESA resistance. To investigate an alternative therapeutic strategy of anemia in ESA-resistant patients, we have conducted a preclinical study of the effects of APG101, a fusion protein consisting of the extracellular domain of human CD95 and the Fc region of human IgG1 on MDS erythropoiesis in vitro. APG101 increases the number of burst-forming unit-erythroid (BFU-E) progenitors derived from CD34+ progenitors in liquid culture and improves overall proliferation rate of erythroid precursors by inhibiting apoptosis. APG101 rescues BFU-E growth in MDS patients presenting with attrition of erythroid progenitors at baseline, independently of CD95 or CD95L expression level. Our data show that overexpression of CD95 at diagnosis is a hallmark of ESA resistance and that severe impairment of erythropoiesis is predictive of erythroid response to APG101 in vitro. These data provide a rationale for further clinical investigation of APG101 in an attempt to treat anemia in lower risk MDS patients.
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Hôpital Cochin, Paris, France.|Université Paris Descartes, Faculté de Médecine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) U1016, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris, France.|Institut Cochin, Department of Development, Reproduction and Cancer, Paris, France.
authors.forename: Anna
authors.initials: A
authors.lastname: Raimbault
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Hôpital Cochin, Paris, France.
authors.forename: Cecile
authors.initials: C
authors.lastname: Pierre-Eugene
authors.affiliation: Département d'Epidémiologie et de Biostatistiques, Hôpitaux Universitaires Paris Centre, Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rouquette
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Hôpital Cochin, Paris, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Deudon
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Clinique, Hôpitaux Universitaires Paris Centre, Hôpital Cochin, Paris, France.
authors.forename: Lise
authors.initials: L
authors.lastname: Willems
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Hôpital Cochin, Paris, France.|Université Paris Descartes, Faculté de Médecine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) U1016, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris, France.|Institut Cochin, Department of Development, Reproduction and Cancer, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chapuis
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Hôpital Cochin, Paris, France.|Université Paris Descartes, Faculté de Médecine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) U1016, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris, France.|Institut Cochin, Department of Development, Reproduction and Cancer, Paris, France.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Mathis
authors.affiliation: APOGENIX, GmbH, Heidelberg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kunz
authors.affiliation: APOGENIX, GmbH, Heidelberg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Fricke
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Hôpital Cochin, Paris, France.|Université Paris Descartes, Faculté de Médecine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) U1016, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris, France.|Institut Cochin, Department of Development, Reproduction and Cancer, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Kosmider
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Hôpital Cochin, Paris, France.|Université Paris Descartes, Faculté de Médecine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) U1016, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris, France.|Institut Cochin, Department of Development, Reproduction and Cancer, Paris, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Bardet
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Hôpital Cochin, Paris, France.|Université Paris Descartes, Faculté de Médecine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) U1016, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris, France.|Institut Cochin, Department of Development, Reproduction and Cancer, Paris, France.
authors.forename: Michaela
authors.initials: M
authors.lastname: Fontenay
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D004920:Erythropoiesis; D005260:Female; D005500:Follow-Up Studies; D006410:Hematopoiesis; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009190:Myelodysplastic Syndromes / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011379:Prognosis; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; C574675:APG101
keywords: CD95; CD95 ligand; anemia; erythropoiesis; myelodysplastic syndromes