A novel natural killer cell line (KHYG-1) from a patient with aggressive natural killer cell leukemia carrying a p53 point mutation

Yagita, Masato; Huang, Cheng-long; Umehara, Hisanori; Matsuo, Yoshinobu; Tabata, Rie; Miyake, Masayuki; Konaka, Yoshiteru; Takatsuki, Kiyoshi

doi:10.1038/sj.leu.2401769

Cited by 173 publications

(133 citation statements)

References 49 publications

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“…130 KHYG-1 cells exhibited greater cytoxicity than NK-92 cells. 134 Irradiated KHYG-1 cells with inhibited proliferation does not diminish their enhanced cytolytic activity against tumor targets, suggesting that KHYG-1 cells may be a feasible anticancer immunotherapeutic agent.…”

Section: Allogeneic Nk Cellsmentioning

confidence: 87%

“…126 Among them, NK-92, KHYG-1, NKL and NKG have been well documented for their antitumor activity, while the other three cell lines YT, NK-YS and HANK-1 are useful for studying the biological characteristics of EBV-associated lymphoma/leukemia. [127][128][129][130] NK-92 cells have been demonstrated to be a safe and potentially beneficial therapy with successful antitumor effects, receiving FDA approval for testing in patients with advanced malignant melanoma and renal cell carcinoma. 46,[131][132][133] NK-92 is currently the only NK cell line that has entered clinical trials and can serve as a platform for studying NK cell-based tumor immunotherapy in the future.…”

Section: Allogeneic Nk Cellsmentioning

confidence: 99%

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NK cell-based immunotherapy for malignant diseases

et al. 2013

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Natural killer (NK) cells play critical roles in host immunity against cancer. In response, cancers develop mechanisms to escape NK cell attack or induce defective NK cells. Current NK cell-based cancer immunotherapy aims to overcome NK cell paralysis using several approaches. One approach uses expanded allogeneic NK cells, which are not inhibited by self histocompatibility antigens like autologous NK cells, for adoptive cellular immunotherapy. Another adoptive transfer approach uses stable allogeneic NK cell lines, which is more practical for quality control and large-scale production. A third approach is genetic modification of fresh NK cells or NK cell lines to highly express cytokines, Fc receptors and/or chimeric tumor-antigen receptors. Therapeutic NK cells can be derived from various sources, including peripheral or cord blood cells, stem cells or even induced pluripotent stem cells (iPSCs), and a variety of stimulators can be used for large-scale production in laboratories or good manufacturing practice (GMP) facilities, including soluble growth factors, immobilized molecules or antibodies, and other cellular activators. A list of NK cell therapies to treat several types of cancer in clinical trials is reviewed here. Several different approaches to NK-based immunotherapy, such as tissue-specific NK cells, killer receptor-oriented NK cells and chemically treated NK cells, are discussed. A few new techniques or strategies to monitor NK cell therapy by non-invasive imaging, predetermine the efficiency of NK cell therapy by in vivo experiments and evaluate NK cell therapy approaches in clinical trials are also introduced.

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Section: Allogeneic Nk Cellsmentioning

confidence: 87%

Section: Allogeneic Nk Cellsmentioning

confidence: 99%

NK cell-based immunotherapy for malignant diseases

et al. 2013

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“…The K562 cells were cultured in RPMI 1640 medium as described previously. 38 Next, an interleukin (IL)-2-dependent human NK cell line bearing a p53 mutation (KHYG-1; Human Science Research Resources Bank, Osaka, Japan) 53 was maintained in the medium with 100 U/mL recombinant IL-2 (Shionogi, Osaka, Japan) and used as cytotoxic effector cells after incubation in the IL-2-depleted medium for 24 hours prior to cytotoxicity assay, as described previously. 38 …”

Section: Cell Culturementioning

confidence: 99%

“…Cultured NK cells (KHYG-1 cell line) lack CD16 (receptor for Fc␥) 53 and do not exert antibody-dependent cellular cytotoxicity (ADCC). Cytotoxicity by KHYG-1 cells was assessed after target K562 cells were preincubated with or without various concentrations of antibodies to NKG2D ligands (ULBPs 1-3, MICA, and MICB) for 1 hour at 37°C.…”

Section: Inhibition Assays With Antibodiesmentioning

confidence: 99%

Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP

Hanaoka

Kawaguchi

Horikawa

et al. 2006

Blood

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The mechanism by which paroxysmal nocturnal hemoglobinuria (PNH) clones expand is unknown. PNH clones harbor PIGA mutations and do not synthesize glycosylphosphatidylinositol (GPI), resulting in deficiency of GPI-linked membrane proteins. GPI-deficient blood cells often expand in patients with aplastic anemia who sustain immune-mediated marrow injury putatively induced by cytotoxic cells, hence suggesting that the injury allows PNH clones to expand selectively. We previously reported that leukemic K562 cells preferentially survived natural killer (NK) cell-mediated cytotoxicity in vitro when they acquired PIGA mutations. We herein show that the survival is ascribable to the deficiency of stress-inducible GPI-linked membrane proteins ULBP1 and ULBP2, which activate NK and T cells. The ULBPs were detected on GPI-expressing but not on GPI-deficient K562 cells. IntroductionParoxysmal nocturnal hemoglobinuria (PNH) is an acquired stem cell disorder of clonal nature characterized by intravascular hemolysis, venous thrombosis, bone marrow (BM) dysfunction, and infrequent development of leukemia. [1][2][3][4] In the last 2 decades, virtually the entire mechanism leading to PNH hemolysis has been elucidated. [5][6][7][8] PNH stem cells acquire PIGA mutations and do not generate glycosylphosphatidylinositol (GPI), resulting in a deficiency of a series of GPI-linked membrane proteins, including complement regulatory molecules such as decay-accelerating factor (DAF) and CD59. PNH cells are then vulnerable to autologous complement. For example, PNH erythrocytes undergo complement-mediated hemolysis. Soon after, the molecular events leading to clinically serious hemolytic precipitation induced by infection were clarified. 9 On the other hand, more than half of patients with PNH show various cytopenias and decreased CD34 ϩ hematopoietic cells. [1][2][3][4][10][11][12] PNH closely associates with aplastic anemia and myelodysplastic syndromes (MDSs) that share BM failure and development of leukemia. 1,12,13 It has been indicated that immune-mediated BM injury underlies at least a part of the diseases. 1,12 Indeed, immunosuppressive therapy ameliorates their marrow failure. 1,12,14,15 Of interest, combination therapy with antithymocyte globulin and cyclosporine A, these immunosuppressants having individual target spectra, 16,17 gives better results than therapy with each 1 of the 2 immunosuppressants. 12,18 In general, both cytotoxic T lymphocytes (CTLs) of adaptive immunity and natural killer (NK) cells of innate immunity operate in combination rather than independently. [19][20][21][22] It is then conceivable that both cytotoxic cells exert critical roles in BM injury, 12,[23][24][25][26] although real features of the autoimmunity have not been delineated.The marked progress in understanding of PNH pathophysiology evokes the next concern about the etiology of PNH, and the mechanisms of both selective expansion of PNH clones 27 and development of leukemia. 28 Above all, we have focused on the expansion of affected cells to mani...

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“…5 However, the mechanisms involved in the pathogenesis and resistance to treatment still remain poorly understood, and the deep research for this special tumor has been hampered by its rarity and insufficient supply of the tumoral samples. 12 Indeed, only a very small number of bona fide NK leukemia-lymphoma cell lines have been described in detail [13][14][15][16] (for review, see Drexler and Matsuo 17 ).…”

Section: Introductionmentioning

confidence: 99%

STAT3 transcription factor is constitutively activated and is oncogenic in nasal-type NK/T-cell lymphoma

et al. 2009

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Nasal-type natural killer (NK) cell lymphoma is an infrequent aggressive malignant disease with very poor prognosis. We aimed to explore the possible role of the transcription factor STAT3 in the pathophysiology of this malignancy, as it was involved in oncogenesis and chemoresistance. For this, we established and characterized a continuous interleukin 2-dependent NK cell line (MEC04) from a patient with a fatal nasal-type NK-cell lymphoma. Cells harbored poor cytotoxic activity against K562 cells, and spontaneously secreted interferon-c, interleukin-10 and vascular-endothelium growth factor in vitro. STAT3 was phosphorylated in Y705 dimerization residue in MEC04 cells and restricted to the nucleus. Y705 STAT3 phosphorylation involved JAK2, as exposure of cells to AG490 inhibitor inhibited Y705 STAT3 phosphorylation. By using recombinant transducible TAT-STAT3-b (b isoform), TAT-STAT3Y705F (a STAT3 protein mutated on Y705 residue, which prevents STAT3 dimerization) and peptides inhibiting specifically STAT3 dimerization, we inhibited STAT3 phosphorylation and cell growth, with cell death induction. Finally, STAT3 was phosphorylated in Y705 residue in the nuclei of lymphoma cells in eight/nine patients with nasal-type NK/T-cell lymphoma and in YT, another NK cell line. Our results suggest that STAT3 protein has a major role in the oncogenic process of nasal-type NK-cell lymphomas, and may represent a promising therapeutical target.

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A novel natural killer cell line (KHYG-1) from a patient with aggressive natural killer cell leukemia carrying a p53 point mutation

Cited by 173 publications

References 49 publications

NK cell-based immunotherapy for malignant diseases

NK cell-based immunotherapy for malignant diseases

Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP

STAT3 transcription factor is constitutively activated and is oncogenic in nasal-type NK/T-cell lymphoma

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