Raimbault Anna, Pierre-Eugene Cecile, Rouquette Alexandra, Deudon Celine, Willems Lise, Chapuis Nicolas, Mathis Stephanie, Kunz Claudia, Fricke Harald, Kosmider Olivier, Bardet Valerie, Fontenay Michaela
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.
Oncotarget. 2016 Mar 22;7(12):14898-911. doi: 10.18632/oncotarget.7469.
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.
CD95是死亡受体家族的一员，当其被配体CD95L激活时，会启动半胱天冬酶依赖性凋亡，据认为这会对骨髓中的红细胞生成产生负调控作用。我们之前已经表明，在三分之二的低危骨髓增生异常综合征（MDS）患者中CD95过度表达，并且对促红细胞生成素（ESA）的耐药性与残余红细胞生成能力差有关。在本研究中，我们表明CD95过度表达和既往输血是ESA耐药性的独立预测因素。为了研究ESA耐药患者贫血的替代治疗策略，我们对APG101（一种由人CD95的细胞外结构域和人IgG1的Fc区域组成的融合蛋白）对体外MDS红细胞生成的影响进行了临床前研究。APG101可增加液体培养中源自CD34+祖细胞的红系爆式集落形成单位（BFU-E）祖细胞数量，并通过抑制凋亡提高红系前体细胞的总体增殖率。APG101可挽救基线时红系祖细胞减少的MDS患者的BFU-E生长，与CD95或CD95L表达水平无关。我们的数据表明，诊断时CD95过度表达是ESA耐药的一个标志，并且红细胞生成的严重受损可预测体外红系对APG101的反应。这些数据为进一步对APG101进行临床研究提供了理论依据，以尝试治疗低危MDS患者的贫血。
