Inhibition of NEMO, the regulatory subunit of the IKK complex, induces apoptosis in high-risk myelodysplastic syndrome and acute myeloid leukemia

In high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), blasts constitutively activate the antiapoptotic transcription factor nuclear factor-kappa B (NF-kappa B). Here, we show that this NF-kappa B activation relies on the constitutive activation of the I kappa B kinase (IKK) complex, which is formed by the IKK alpha, IKK beta and IKK gamma/NF-kappa B essential modulator (NEMO) subunits. A cell-permeable peptide that mimics the leucine zipper subdomain of IKK gamma, thus preventing its oligomerization, inhibited the constitutive NF-kappa B activation and induced apoptotic cell death in a panel of human MDS and AML cell lines (P39, MOLM13, THP1 and MV4-11). Small interfering RNA-mediated knockdown of the p65 NF-kappa B subunit or the three IKK subunits including IKK gamma/NEMO also induced apoptotic cell death in P39 cells. Cell death induced by the IKK gamma/NEMO-antagonistic peptide involved the caspase-independent loss of the mitochondrial transmembrane potential as well as signs of outer mitochondrial membrane permeabilization with the consequent release of cytochrome c, apoptosis-inducing factor and endonuclease G. Primary bone marrow CD34(+) cells from high-risk MDS and AML patients also succumbed to the IKK gamma/NEMO-antagonistic peptide, but not to a mutated control peptide. Altogether, these data indicate that malignant cells in high-risk MDS and AML cells critically depend on IKK gamma/NEMO to survive. Moreover, our data delineate a novel procedure for their therapeutic removal, through inhibition of IKK gamma/NEMO oligomerization.