title: Bioimaging analysis of nuclear factor-κB activity in Philadelphia chromosome-positive acute lymphoblastic leukemia cells reveals its synergistic upregulation by tumor necrosis factor-α-stimulated changes to the microenvironment.
abstract: To gain an insight into the microenvironmental regulation of nuclear factor (NF)-κB activity in the progression of leukemia, we established a bioluminescent imaging model of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) cells transduced with a NF-κB/luciferase (Luc) reporter and cocultured with murine stromal cells and cytokines. Stromal cells alone did not augment Luc activity, taken as an index of NF-κB, but Luc activity was synergistically upregulated by the combination of stromal cells and tumor necrosis factor (TNF)-α. Dehydroxymethylepoxyquinomicin (DHMEQ), a specific inhibitor of NF-κB DNA binding, rapidly induced the apoptosis of Ph+ALL cells, indicating that NF-κB is necessary for the growth and survival of these cells. However, the DHMEQ-induced suppression of NF-κB activity and the apoptosis of leukemia cells were attenuated by the presence of stromal cells and TNF-α. In NOD-SCID mice transplanted with NF-κB/Luc reporter-containing Ph+ALL cell lines and monitored periodically during the progression of the leukemia, murine TNF-α was significantly expressed in lesions in which the leukemia cells emitted a significant NF-κB signal. These results support the notion that TNF-α also triggers microenvironmental upregulation of NF-κB activity in vivo. Collectively, the results indicated that TNF-α-stimulated microenvironment may contribute to the survival and progression of Ph+ALL cells through the synergistic upregulation of NF-κB activity.
authors.affiliation: Division of Molecular Therapy, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hui-Jen
authors.initials: HJ
authors.lastname: Tsai
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Izawa
authors.forename: Takaomi
authors.initials: T
authors.lastname: Ishida
authors.forename: Toshiki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Sheng-Fung
authors.initials: SF
authors.lastname: Lin
authors.forename: Arinobu
authors.initials: A
authors.lastname: Tojo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D001853:Bone Marrow / Q000378:metabolism; D045744:Cell Line, Tumor / Q000378:metabolism; D003512:Cyclohexanones / Q000494:pharmacology; D018450:Disease Progression; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D017930:Genes, Reporter; D006801:Humans; D000068877:Imatinib Mesylate; D008163:Luminescent Measurements; D051379:Mice; D016328:NF-kappa B / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011743:Pyrimidines / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D013154:Spleen / Q000378:metabolism; D017154:Stromal Cells / Q000502:physiology; D019076:Transgenes; D014183:Transplantation, Heterologous; D047368:Tumor Burden; D059016:Tumor Microenvironment / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D003512:Cyclohexanones; D016328:NF-kappa B; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C464444:dehydroxymethylepoxyquinomicin; D000068877:Imatinib Mesylate