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-kappaB (NF-kappaB). Here, we show that this NF-kappaB activation relies on the constitutive activation of the IkappaB kinase (IKK) complex, which is formed by the IKKalpha, IKKbeta and IKKgamma/NF-kappaB essential modulator (NEMO) subunits. A cell-permeable peptide that mimics the leucine zipper subdomain of IKKgamma, thus preventing its oligomerization, inhibited the constitutive NF-kappaB 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-kappaB subunit or the three IKK subunits including IKKgamma/NEMO also induced apoptotic cell death in P39 cells. Cell death induced by the IKKgamma/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 IKKgamma/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 IKKgamma/NEMO to survive. Moreover, our data delineate a novel procedure for their therapeutic removal, through inhibition of IKKgamma/NEMO oligomerization.
Carvalho
G
G
INSERM, Unit Apoptosis, Cancer and Immunity, Villejuif, France.
Fabre
C
C
Braun
T
T
Grosjean
J
J
Ades
L
L
Agou
F
F
Tasdemir
E
E
Boehrer
S
S
Israel
A
A
Véron
M
M
Fenaux
P
P
Kroemer
G
G
D000208:Acute Disease; D000595:Amino Acid Sequence; D017209:Apoptosis; D045744:Cell Line, Tumor; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D007951:Leukemia, Myeloid / Q000473:pathology*; D008969:Molecular Sequence Data; D009190:Myelodysplastic Syndromes / Q000473:pathology*; D016328:NF-kappa B / Q000502:physiology; D010446:Peptide Fragments / Q000737:chemistry; D021122:Protein Subunits; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection
C491731:IKBKG protein, human; D016328:NF-kappa B; D010446:Peptide Fragments; D021122:Protein Subunits; D034741:RNA, Small Interfering; D051550:I-kappa B Kinase