Increased IκB kinase activity is associated with activated NF-κB in acute myeloid blasts

Baumgartner, Bastian; Weber, Marion; Quirling, Martina; Fischer, Cornelius; Page, Sharon; Adam, Mike; Schilling, Christoph von; Waterhouse, Christine; Schmid, Christoph; Neumeier, D.; Brand, Korbinian

doi:10.1038/sj.leu.2402641

Cited by 83 publications

(67 citation statements)

References 45 publications

(96 reference statements)

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“…For example, NF-kB activation and increased IKK activity are found in blasts and stem cells associated with acute myelogenous leukemia (AML) (Baumgartner et al, 2002). Consistent with this, NF-kB activation is detected in the bone marrow of patients with myelodysplastic syndrome (Braun et al, 2006), which is considered a precursor disease of AML.…”

Section: Nf-kb In Hematologic Malignanciesmentioning

confidence: 66%

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

2006

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Section: Nf-kb In Hematologic Malignanciesmentioning

confidence: 66%

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

2006

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“…73 The molecular mechanism of NF-kB activation in LSCs or AML blasts remains elusive. Constitutive activation of the NF-kB complex via dysregulation of IKK signalling has been described recently in LSC and AML blasts from the bone marrow and peripheral blood in two studies enrolling 35 74 and 18 patients, respectively. 73 One report provided evidence for high IKK kinase activity leading to NF-kB activation independently from IkBa expression.…”

Section: Myelodysplastic Syndromesmentioning

confidence: 90%

“…73 One report provided evidence for high IKK kinase activity leading to NF-kB activation independently from IkBa expression. 74 The second report revealed that specific targeting of IKKb with a pharmacologic inhibitor could block constitutive NF-kB activity leading to apoptosis via hypophosphorylation of IKKb, underlying the role of IKK as pacemaker for constitutive NF-kB activity in LSC and AML blasts. 73 Meanwhile, the reasons for IKK activation in AML are still to be elucidated.…”

Section: Myelodysplastic Syndromesmentioning

confidence: 99%

Targeting NF-κB in hematologic malignancies

et al. 2006

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The transcription factor nuclear factor kappa B (NF-jB) can intervene in oncogenesis by virtue of its capacity to regulate the expression of a plethora of genes that modulate apoptosis, and cell survival as well as proliferation, inflammation, tumor metastasis and angiogenesis. Different reports demonstrate the intrinsic activation of NF-jB in lymphoid and myeloid malignancies, including preneoplastic conditions such as myelodysplastic syndromes, underscoring its implication in malignant transformation. Targeting intrinsic NF-jB activation, as well as its upstream and downstream regulators, may hence constitute an additional approach to the oncologist's armamentarium. Several small inhibitors of the NF-jB-activatory kinase IjB kinase, of the proteaseome, or of the DNA binding of NF-jB subunits are under intensive investigation. Currently used cytotoxic agents can induce NF-jB activation as an unwarranted side effect, which confers apoptosis suppression and hence resistance to these drugs. Thus, NF-jB inhibitory molecules may be clinically useful, either as single therapeutic agents or in combination with classical chemotherapeutic agents, for the treatment of hematological malignancies.

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“…The IkBs are then polyubiquitinated and degraded by the proteasome, therefore allowing nuclear translocation of the NF-kB dimers and activation of their target genes. IKK can be activated by multiple intra-and extracellular stimuli (Karin et al, 2004), and the inhibition of IKK by inhibitors of the catalytic IKK subunits IKKa and IKKb can induce apoptosis in MDS and AML cell lines (Baumgartner et al, 2002;Braun et al, 2006a).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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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.

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Increased IκB kinase activity is associated with activated NF-κB in acute myeloid blasts

Cited by 83 publications

References 45 publications

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

Targeting NF-κB in hematologic malignancies

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

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