title: [NF-κB activity in myeloid leukemia stem cells].
abstract: Acute myeloid leukemia (AML) is a hematologic malignancy which originates from leukemia initiating cells (LICs). Since LICs are considered to be resistant to standard chemotherapy, the identification of common mechanisms involved in LIC maintenance and progression is crucial to establishing broadly effective therapeutic agents for AML. The NF-κB pathway is one of the most promising targets, considering that its constitutive activation has been reported in different types of AML. In myeloid leukemia mouse models, we found that NF-κB activity is maintained specifically in LICs through autocrine TNF-α secretion, forming an NF-κB/TNF-α positive feedback loop. LICs had increased levels of active proteasome machinery, which promoted the degradation of IκBα and further supported NF-κB activity. Genetic ablation of TNF-α or NF-κB markedly suppressed leukemia progression in vivo. These findings demonstrate that NF-κB/TNF-α signaling in LICs contributes to leukemia progression and provide a widely applicable approach for targeting LICs.
authors.affiliation: Princess Margaret Cancer Centre, University Health Network.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kagoya
mesh_terms: D000818:Animals; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D017346:Protein Serine-Threonine Kinases