NF-{kappa}B constitutes a potential therapeutic target in high-risk myelodysplastic syndromes.
Blood. 2005 Oct 13; [Epub ahead of print]
Braun T, Carvalho G, Coquelle A, Vozenin MC, Lepelley P, Hirsch F, Kiladjian JJ, Ribrag V, Fenaux P, Kroemer G.
Centre National de la Recherche Scientifique, UMR8125, Institut Gustave Roussy, Villejuif, France.
MDS is a preneoplastic condition that frequently develops into overt 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 downregulation 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, 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-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. |
