title: Differentiating megakaryocytes in myelodysplastic syndromes succumb to mitochondrial derangement without caspase activation.
abstract: 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.
authors.affiliation: INSERM, Unit 848, F-94805 Villejuif, France.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Braun
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Carvalho
authors.forename: Jennifer
authors.initials: J
authors.lastname: Grosjean
authors.forename: Lionel
authors.initials: L
authors.lastname: Ades
authors.forename: Claire
authors.initials: C
authors.lastname: Fabre
authors.forename: Simone
authors.initials: S
authors.lastname: Boehrer
authors.forename: Najet
authors.initials: N
authors.lastname: Debili
authors.forename: Pierre
authors.initials: P
authors.lastname: Fenaux
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D001854:Bone Marrow Cells / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism*; D016923:Cell Death; D002454:Cell Differentiation; D004789:Enzyme Activation; D006801:Humans; D008533:Megakaryocytes / Q000473:pathology*; D008928:Mitochondria / Q000473:pathology*; D009190:Myelodysplastic Syndromes / Q000473:pathology*
chemical_list: D053148:Caspase 3