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

Abstract

In high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), blasts constitutively activate the antiapoptotic transcription factor nuclear factor-jB (NF-jB). Here, we show that this NF-jB activation relies on the constitutive activation of the IjB kinase (IKK) complex, which is formed by the IKKa, IKKb and IKKc/ NF-jB essential modulator (NEMO) subunits. A cellpermeable peptide that mimics the leucine zipper subdomain of IKKc, thus preventing its oligomerization, inhibited the constitutive NF-jB 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-jB subunit or the three IKK subunits including IKKc/NEMO also induced apoptotic cell death in P39 cells. Cell death induced by the IKKc/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 þ cells from high-risk MDS and AML patients also succumbed to the IKKc/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 IKKc/NEMO to survive. Moreover, our data delineate a novel procedure for their therapeutic removal, through inhibition of IKKc/NEMO oligomerization.

Histone Deacetylase Inhibitors Activate NF-κB in Human Leukemia Cells through an ATM/NEMO-related Pathway

“…Interestingly, ATM and NEMO have recently been implicated in the constitutive NF-B activation characteristic of certain malignant hematopoietic cells (e.g. acute myeloid leukemia and myelodysplastic syndrome cells) (58,60). Thus, interference with ATM (e.g.…”

NF-κB inhibition sensitizes to starvation-induced cell death in high-risk myelodysplastic syndrome and acute myeloid leukemia

“…constitutive NF-kB activation but, moreover, critically depend on this NF-kB activation, as demonstrated by the fact that its inhibition causes their immediate apoptosis (Carvalho et al, 2006;Braun et al, 2006b). Very similar data have been reported on AML, irrespective of the etiology of the disease (which may be primary, post-MDS or secondary to chemotherapy of other malignancies).…”

ATM mediates constitutive NF-κB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia

“…In addition, ATM depletion caused cell death, as indicated by the loss of DC m and plasma membrane integrity. This proapoptotic effect of ATM knockdown could not be further enhanced by depleting p65, NEMO or PIDD with two confirmed siRNAs each (Lin et al, 2000b;Braun et al, 2006a;Carvalho et al, 2007;Figure 4d). This kind of epistatic analysis confirms that ATM is required for the constitutive activation of NF-kB in P39 cells and suggests that the proapoptotic effect of ATM depletion is mediated through NF-kB inactivation.…”

“…In contrast, in high-risk MDS, apoptosis is suppressed because of a variety of factors including the constitutive activation of nuclear factor-kB (NF-kB) in malignant myeloblasts (Braun et al, 2006b;Carvalho et al, 2007). NF-kB acts as a mitogenic, anti-apoptotic transcription factor, and its inhibition kills high-risk MDS myeloblasts (Guzman et al, 2001;Birkenkamp et al, 2004), which hence are 'addicted' to NF-kB.…”