Oncotarget

Research Papers:

APG101 efficiently rescues erythropoiesis in lower risk myelodysplastic syndromes with severe impairment of hematopoiesis

Anna Raimbault, Cecile Pierre-Eugene, Alexandra Rouquette, Celine Deudon, Lise Willems, Nicolas Chapuis, Stephanie Mathis, Claudia Kunz, Harald Fricke, Olivier Kosmider, Valerie Bardet, Michaela Fontenay _ and on behalf of the Groupe Francophone des Myélodysplasies

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Oncotarget. 2016; 7:14898-14911. https://doi.org/10.18632/oncotarget.7469

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Abstract

Anna Raimbault1,2,3,4,5,*, Cecile Pierre-Eugene1,*, Alexandra Rouquette6, Celine Deudon1, Lise Willems7, Nicolas Chapuis1,2,3,4,5, Stephanie Mathis1,2,3,4,5, Claudia Kunz8, Harald Fricke8, Olivier Kosmider1,2,3,4,5, Valerie Bardet1,2,3,4,5, Michaela Fontenay1,2,3,4,5, on behalf of the Groupe Francophone des Myélodysplasies

1Assistance Publique-Hôpitaux de Paris, Service d’Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Hôpital Cochin, Paris, France

2Université Paris Descartes, Faculté de Médecine, Paris, France

3Institut National de la Santé et de la Recherche Médicale (INSERM) U1016, Paris, France

4Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris, France

5Institut Cochin, Department of Development, Reproduction and Cancer, Paris, France

6Département d’Epidémiologie et de Biostatistiques, Hôpitaux Universitaires Paris Centre, Paris, France

7Assistance Publique-Hôpitaux de Paris, Service d’Hématologie Clinique, Hôpitaux Universitaires Paris Centre, Hôpital Cochin, Paris, France

8APOGENIX, GmbH, Heidelberg, Germany

*These authors have contributed equally to this work

Correspondence to:

Michaela Fontenay, e-mail: [email protected]

Keywords: myelodysplastic syndromes, erythropoiesis, CD95, CD95 ligand, anemia

Received: September 07, 2015    Accepted: January 02, 2016    Published: February 18, 2016

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.


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