title: NF-kappaB constitutes a potential therapeutic target in high-risk myelodysplastic syndrome.
abstract: 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-kappaB activation. In this cell line, NF-kappaB inhibition by small interfering RNAs specific for p65 or chemical inhibitors including bortezomib resulted in the down-regulation of apoptosis-inhibitory NF-kappaB 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-kappaB 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-kappaB subunit. The frequency of cells with nuclear p65 correlated with blast counts, apoptosis suppression, and disease progression. NF-kappaB activation was confined to those cells that carried MDS-associated cytogenetic alterations. Since NF-kappaB inhibition induced rapid apoptosis of bone marrow cells from high-risk MDS patients, we postulate that NF-kappaB activation is responsible for the progressive suppression of apoptosis affecting differentiating MDS cells and thus contributes to malignant transformation. NF-kappaB inhibition may constitute a novel therapeutic strategy if apoptosis induction of MDS stem cells is the goal.
authors.affiliation: Centre National de la Recherche Scientifique, Unite Mixté de Recherche (UMR) 8125, Institut Gustave Roussy, Villejuif, France.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Braun
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Carvalho
authors.forename: Arnaud
authors.initials: A
authors.lastname: Coquelle
authors.forename: Marie-Catherine
authors.initials: MC
authors.lastname: Vozenin
authors.forename: Pascale
authors.initials: P
authors.lastname: Lepelley
authors.forename: François
authors.initials: F
authors.lastname: Hirsch
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Kiladjian
authors.forename: Vincent
authors.initials: V
authors.lastname: Ribrag
authors.forename: Pierre
authors.initials: P
authors.lastname: Fenaux
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002869:Chromosome Aberrations; D045304:Cytochromes c / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000201:enzymology / Q000473:pathology; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000378:metabolism*; D023461:Myeloid Progenitor Cells / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology*; D012307:Risk Factors; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D051033:Apoptosis Inducing Factor; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D045304:Cytochromes c; D004706:Endodeoxyribonucleases; C052391:endonuclease G