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Blood, 1 February 2006, Vol. 107, No. 3, pp. 1156-1165. Prepublished online as a Blood First Edition Paper on October 13, 2005; DOI 10.1182/blood-2005-05-1989. This Article Full Text (PDF) All Versions of this Article: 2005-05-1989v1 107/3/1156    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Braun, T. Articles by Kroemer, G. Search for Related Content PubMed PubMed Citation Articles by Braun, T. Articles by Kroemer, G. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 18, 2005 Accepted September 25, 2005 NF-B constitutes a potential therapeutic target in high-risk myelodysplastic syndromes Thorsten Braun, Gabrielle Carvalho, Arnauld Coquelle, Marie-Catherine Vozenin, Pascale Lepelley, Francois Hirsch, Jean-Jacques Kiladjian, Vincent Ribrag, Pierre Fenaux, and Guido Kroemer* Centre National de la Recherche Scientifique, UMR8125, Institut Gustave Roussy, Villejuif, France UPRES EA 2710, Institut Gustave Roussy, Villejuif, France Laboratoire d'Hematologie, Hopital Calmette, Lille, France INSERM-U542, Paris XI University, Hopital Paul Brousse, Villejuif, France Service d'Hematologie Clinique, Hopital Avicenne, AP-HP, Universite Paris, Bobigny, France Service d'Hematologie Clinique, Institut Gustave Roussy, Villejuif, France * Corresponding author; email: kroemer{at}igr.fr. MDS is a preneoplastic condition that frequently develops into overt AML. The P39 MDS/AML cell line manifested constitutive NF-B-activation. In this cell line, NF-B -inhibition by small interfering RNAs specific for p65 or chemical inhibitors including bortezomib resulted in the downregulation of apoptosis-inhibitory NF-B target genes and subsequent cell death, accompanied by loss of mitochondrial transmembrane potential as well as by the mitochondrial release of the caspase activator cytochrome c and the caspase-independent death effectors endonuclease G and apoptosis inducing factor (AIF). Bone marrow cells from high-risk MDS patients also exhibited constitutive NF-B-activation, similarly as bone marrow samples from MDS-AML patients. Purified hematopoietic stem cells (CD34+) and immature myeloid cells (CD33+) from high-risk MDS patients demonstrated the nuclear translocation of the p65 NF-B subunit. The frequency of cells with nuclear p65 correlated with blast counts, apoptosis suppression and disease progression. NF-B-activation was confined to those cells that carried MDS-associated cytogenetic alterations. Since NF-B-inhibition induced rapid apoptosis of bone marrow cells from high-risk MDS patients, we postulate that NF-B-activation is responsible for the progressive suppression of apoptosis affecting differentiating MDS cells and thus contributes to malignant transformation. NF-B-inhibition may constitute a novel therapeutic strategy if apoptosis induction of MDS stem cells is the goal. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Boehrer, L. Ades, T. Braun, L. Galluzzi, J. Grosjean, C. Fabre, G. Le Roux, C. Gardin, A. Martin, S. de Botton, et al. Erlotinib exhibits antineoplastic off-target effects in AML and MDS: a preclinical study Blood, February 15, 2008; 111(4): 2170 - 2180. [Abstract] [Full Text] [PDF] D. Briot, G. Mace-Aime, F. Subra, and F. 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