title: Positive feedback between NF-κB and TNF-α promotes leukemia-initiating cell capacity.
abstract: Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy that originates from leukemia-initiating cells (LICs). The identification of common mechanisms underlying LIC development will be important in establishing broadly effective therapeutics for AML. Constitutive NF-κB pathway activation has been reported in different types of AML; however, the mechanism of NF-κB activation and its importance in leukemia progression are poorly understood. Here, we analyzed myeloid leukemia mouse models to assess NF-κB activity in AML LICs. We found that LICs, but not normal hematopoietic stem cells or non-LIC fractions within leukemia cells, exhibited constitutive NF-κB activity. This activity was maintained through autocrine TNF-α secretion, which formed 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. Pharmacological inhibition of the proteasome complex markedly suppressed leukemia progression in vivo. Conversely, enhanced activation of NF-κB signaling expanded LIC frequency within leukemia cell populations. We also demonstrated a strong correlation between NF-κB activity and TNF-α secretion in human AML samples. Our findings indicate that NF-κB/TNF-α signaling in LICs contributes to leukemia progression and provide a widely applicable approach for targeting LICs.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kagoya
authors.forename: Akihide
authors.initials: A
authors.lastname: Yoshimi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kataoka
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Keiki
authors.initials: K
authors.lastname: Kumano
authors.forename: Shunya
authors.initials: S
authors.lastname: Arai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Taku
authors.initials: T
authors.lastname: Saito
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Mineo
authors.initials: M
authors.lastname: Kurokawa
mesh_terms: D021581:Active Transport, Cell Nucleus; D000328:Adult; D000368:Aged; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D018450:Disease Progression; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D007938:Leukemia / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry; D011719:Pyrazines / Q000627:therapeutic use; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D001897:Boronic Acids; D016328:NF-kappa B; D011719:Pyrazines; D014409:Tumor Necrosis Factor-alpha; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex