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.
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Abbreviations
- AIF:
-
apoptosis inducing factor
- AML:
-
acute myeloid leukemia
- BMMNC:
-
bone marrow mononuclear cells
- Casp-3a:
-
activated caspase-3
- Cyt c :
-
cytochrome c
- DiOC6(3):
-
3,3′ dihexyloxacarbocyanine iodide
- EndoG:
-
endonuclease G
- Hsp60:
-
heat shock protein 60
- IPSS:
-
international prognostic scoring system
- MDS:
-
myelodysplastic syndrome
- MK:
-
megakaryocytes
- MMP:
-
mitochondrial membrane permeabilization
- PI:
-
propidium iodide
- VWF:
-
Willebrand factor (Factor VIII)
- z-VAD.fmk:
-
N-benzyloxycarbonyl-Val-Ala-Asp- fluoromethylketone
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Acknowledgments
This work was supported by Cancéropôle Ile-de-France, Association pour la recherche sur le cancer, Fondation de France, Association Laurette Fugain, European Community (Active p53, TransDeath) (G.K.) and MDS Foundation (T.B.). T.B., J.G., C.F. and S.B. are supported by fellowships from the Etablissement Français du Sang, the Institut National du Cancer, the Fondation pour la Recherche Médicale and Deutsche Forschungsgemeinschaft, respectively.
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T. Braun and G. Carvalho contributed equally to this paper.
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Braun, T., Carvalho, G., Grosjean, J. et al. Differentiating megakaryocytes in myelodysplastic syndromes succumb to mitochondrial derangement without caspase activation. Apoptosis 12, 1101–1108 (2007). https://doi.org/10.1007/s10495-006-0030-z
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DOI: https://doi.org/10.1007/s10495-006-0030-z