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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 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 Citation Map 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. Related Collections Neoplasia Apoptosis Signal Transduction Stem Cells in Hematology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA NF-B constitutes a potential therapeutic target in high-risk myelodysplastic syndrome Thorsten Braun, Gabrielle Carvalho, Arnaud Coquelle, Marie-Catherine Vozenin, Pascale Lepelley, François Hirsch, Jean-Jacques Kiladjian, Vincent Ribrag, Pierre Fenaux, and Guido Kroemer From the Centre National de la Recherche Scientifique, Unite Mixté de Recherche (UMR) 8125, Institut Gustave Roussy, Villejuif, France; Unité propre de la recherche et de l'enseignement superieur (UPRES EA) 2710, Institut Gustave Roussy, Villejuif, France; Laboratoire d'Hématologie, Hôpital Calmette, Lille, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U542, Paris XI University, Hôpital Paul Brousse, Villejuif, France; Service d'Hématologie Clinique, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris 13, Bobigny, France; and Service d'Hématologie Clinique, Institut Gustave Roussy, Villejuif, France. Myelodysplastic syndrome (MDS) is a preneoplastic condition that frequently develops into overt acute myeloid leukemia (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 down-regulation 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 similar to 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: F. Delhommeau, S. Dupont, V. D. Valle, C. James, S. Trannoy, A. Masse, O. Kosmider, J.-P. Le Couedic, F. Robert, A. Alberdi, et al. Mutation in TET2 in Myeloid Cancers N. Engl. J. Med., May 28, 2009; 360(22): 2289 - 2301. [Abstract] [Full Text] [PDF] R. K. 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