Braun Thorsten, Carvalho Gabrielle, Grosjean Jennifer, Ades Lionel, Fabre Claire, Boehrer Simone, Debili Najet, Fenaux Pierre, Kroemer Guido
INSERM, Unit 848, F-94805 Villejuif, France.
Apoptosis. 2007 Jun;12(6):1101-8. doi: 10.1007/s10495-006-0030-z.
Myelodysplastic syndromes (MDS) constitute a preneoplastic condition in which potentially malignant cancer stem cells continuously die during differentiation. This MDS-associated cell death often involves caspase-3 activation, yet can also occur without caspase activation, for instance in differentiating megakaryocytes (MK). We investigated, the mechanisms through which MK from MDS patients undergo premature cell death. While polyploid, mature MK from healthy subjects or MDS patients manifested caspase-3 activation during terminal differentiation, freshly isolated, immature MK from MDS died without caspase-3 activation. Similarly, purified bone marrow CD34(+) cells from MDS patients that were driven into MK differentiation in vitro died without caspase-3 activation at an immature stage, before polyploidization. The premature death of MDS MK was accompanied by the mitochondrial release of cytochrome c, Smac/DIABLO and endonuclease G, a caspase-independent death effector, as well loss of the mitochondrial membrane potential and plasma membrane phosphatidylserine exposure before definitive loss of viability. Thus, a stereotyped pattern of mitochondrial alterations accompanies differentiation-associated MK death in MDS.
骨髓增生异常综合征（MDS）是一种肿瘤前状态，其中潜在的恶性癌症干细胞在分化过程中持续死亡。这种与MDS相关的细胞死亡通常涉及半胱天冬酶-3的激活，但也可在无半胱天冬酶激活的情况下发生，例如在分化的巨核细胞（MK）中。我们研究了MDS患者的MK发生过早细胞死亡的机制。虽然来自健康受试者或MDS患者的多倍体成熟MK在终末分化过程中表现出半胱天冬酶-3的激活，但从MDS患者新鲜分离的未成熟MK在无半胱天冬酶-3激活的情况下死亡。同样，来自MDS患者的纯化骨髓CD34(+)细胞在体外被诱导分化为MK时，在未成熟阶段、多倍体化之前，在无半胱天冬酶-3激活的情况下死亡。MDS MK的过早死亡伴随着细胞色素c、Smac/DIABLO和核酸内切酶G（一种不依赖半胱天冬酶的死亡效应物）从线粒体释放，以及在最终丧失活力之前线粒体膜电位丧失和质膜磷脂酰丝氨酸暴露。因此，在MDS中，一种固定模式的线粒体改变伴随着与分化相关的MK死亡。
