APO-1-induced apoptosis of leukemia cells from patients with adult T- cell leukemia

Abstract The 48-Kd cell-surface protein APO-1 is a new member of the nerve growth factor (NGF)/tumor necrosis factor (TNF) receptor superfamily. APO-1 is expressed on various cells, including activated T and B cells and some lymphoid and nonlymphoid cell lines. Triggering of APO-1 by the monoclonal antibody anti-APO-1 induces programmed cell death (apoptosis) in APO-1-expressing cells. APO-1 is also present on T-cell lines derived from patients with adult T-cell leukemia (ATL). Therefore, we investigated APO-1 expression and APO-1-mediated induction of apoptosis ex vivo in cells from patients with ATL. Fresh leukemic cells from nine patients with ATL were assayed for APO-1 expression by two-color immunofluorescence. The leukemic cells from all patients strongly expressed APO-1. Incubation of ATL cells with anti- APO-1 in vitro inhibited spontaneous and cytokine-mediated DNA synthesis. Furthermore, DNA isolated from cells treated with anti-APO-1 exhibited polynucleosomal DNA fragmentation (DNA ladder) characteristic for apoptotic cell death. The analysis of APO-1-mediated apoptosis may represent a new approach to the study of growth control in lymphoid malignancies. In addition, induction of apoptosis by administration of anti-APO-1 may represent a new therapeutic approach for aggressive T- cell malignancies such as ATL.

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APO-1-induced apoptosis of leukemia cells from patients with adult T- cell leukemia

Blood ◽

10.1182/blood.v81.11.2972.bloodjournal81112972 ◽

1993 ◽

Vol 81 (11) ◽

pp. 2972-2977 ◽

Cited By ~ 1

Author(s):

KM Debatin ◽

CK Goldman ◽

TA Waldmann ◽

PH Krammer

Keyword(s):

Cell Death ◽

T Cell ◽

Cell Lines ◽

Ex Vivo ◽

Apoptotic Cell ◽

Leukemic Cells ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

Induction Of Apoptosis

The 48-Kd cell-surface protein APO-1 is a new member of the nerve growth factor (NGF)/tumor necrosis factor (TNF) receptor superfamily. APO-1 is expressed on various cells, including activated T and B cells and some lymphoid and nonlymphoid cell lines. Triggering of APO-1 by the monoclonal antibody anti-APO-1 induces programmed cell death (apoptosis) in APO-1-expressing cells. APO-1 is also present on T-cell lines derived from patients with adult T-cell leukemia (ATL). Therefore, we investigated APO-1 expression and APO-1-mediated induction of apoptosis ex vivo in cells from patients with ATL. Fresh leukemic cells from nine patients with ATL were assayed for APO-1 expression by two-color immunofluorescence. The leukemic cells from all patients strongly expressed APO-1. Incubation of ATL cells with anti- APO-1 in vitro inhibited spontaneous and cytokine-mediated DNA synthesis. Furthermore, DNA isolated from cells treated with anti-APO-1 exhibited polynucleosomal DNA fragmentation (DNA ladder) characteristic for apoptotic cell death. The analysis of APO-1-mediated apoptosis may represent a new approach to the study of growth control in lymphoid malignancies. In addition, induction of apoptosis by administration of anti-APO-1 may represent a new therapeutic approach for aggressive T- cell malignancies such as ATL.

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Adult T-Cell Leukemia: Challenge for Induction of Apoptosis in Leukemic Cells

Internal Medicine ◽

10.2169/internalmedicine.35.167 ◽

1996 ◽

Vol 35 (3) ◽

pp. 167-168

Author(s):

Hitoshi SUZUSHIMA ◽

Kazunari YAMAGUCHI

Keyword(s):

T Cell ◽

Leukemic Cells ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

Induction Of Apoptosis

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Genistein Induced Apoptotic Cell Death in Adult T-Cell Leukemia Cells through Estrogen Receptors

Bioscience Biotechnology and Biochemistry ◽

10.1271/bbb.100359 ◽

2010 ◽

Vol 74 (10) ◽

pp. 2113-2115 ◽

Cited By ~ 17

Author(s):

Masao YAMASAKI ◽

Ayako MUKAI ◽

Masayo OHBA ◽

Yoshihiro MINE ◽

Yoichi SAKAKIBARA ◽

...

Keyword(s):

Cell Death ◽

T Cell ◽

Estrogen Receptors ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Leukemia Cells ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia

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Expression of Tumor Invasion Factors Determines Systemic Engraftment and Induction of Humoral Hypercalcemia in a Mouse Model of Adult T-cell Leukemia

Veterinary Pathology ◽

10.1354/vp.08-vp-0254-n-fl ◽

2009 ◽

Vol 46 (5) ◽

pp. 1003-1014 ◽

Cited By ~ 12

Author(s):

C. Parrula ◽

B. Zimmerman ◽

P. Nadella ◽

S. Shu ◽

T. Rosol ◽

...

Keyword(s):

T Cell ◽

Cell Lines ◽

Leukemic Cells ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Humoral Hypercalcemia Of Malignancy ◽

Cell Leukemia Virus Type ◽

Hypercalcemia Of Malignancy ◽

Adult T Cell Leukemia ◽

Humoral Hypercalcemia

Infection with human T-cell leukemia virus type 1 (HTLV-1) leads sometimes to the development of adult T-cell lymphoma/leukemia (ATL), which is invariably fatal and often associated with humoral hypercalcemia of malignancy. The transformation of infected CD4 T cells and the pathogenesis of leukemia have been studied with great limitation in tissue culture and patients. To better understand the pathogenesis and perform preclinical drug studies, animal models of ATL are urgently needed. In mice, inoculation of HTLV-1 cell lines mostly leads to development of localized lymphomas. To develop an ATL animal model with leukemic spread of ATL cells, mouse strains with different well-defined immune deficiencies were inoculated intraperitoneally with different HTLV-1infected cell lines (ACH.2, C8166, MT-2, MET-1). Inoculation of MET-1 cells into NOD/SCID mice provided the best model system for slowly developing T-cell leukemia with multiple organ involvement. In leukemic mice, an increase in serum calcium levels correlated with expression of receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cells ligand on leukemic cells and secretion of parathyroid hormone-related protein and interleukin-6. In contrast to the other cell lines that did not spread systemically, MET-1 expressed both the adhesion molecules CDlla (LFA-lot) and CD49d (VLA-4ot) and produced or induced expression of matrix metalloproteinases 1, 2, 3, and 9, thus underlining the importance of these molecules in the spread of adult T-cell leukemia cells. The MET-1/NOD/SCID model will be useful for developing interventions against invasion and spread of leukemic cells and subsequent humoral hypercalcemia of malignancy.

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Deregulation of microRNA involved in hematopoiesis and the immune response in HTLV-I adult T-cell leukemia

Blood ◽

10.1182/blood-2008-11-189845 ◽

2009 ◽

Vol 113 (20) ◽

pp. 4914-4917 ◽

Cited By ~ 102

Author(s):

Marcia Bellon ◽

Yves Lepelletier ◽

Olivier Hermine ◽

Christophe Nicot

Keyword(s):

T Cell ◽

Cell Lines ◽

Ex Vivo ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Hematopoietic Stem ◽

Adult T Cell Leukemia ◽

Infected Cells

Human T-cell leukemia virus type-I (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL), an aggressive lymphoproliferative disease. MicroRNAs (miRNAs) are differentially expressed during hematopoiesis and lineage commitment of hematopoietic stem cell progenitors (HSCPs). Here, we report aberrant expression of hematopoietic-specific miR-223, miR-181a, miR-150, miR-142.3p, and miR-155 in HTLV-I–infected cells in vitro and uncultured ex vivo ATL cells. Our results suggest that HTLV-I–infected cells have an unbalanced expression of miRNA that favors T-cell differentiation. We also found altered expression of miRNA previously recognized as innate immunity regulators: miR-155, miR-125a, miR-132, and miR-146. Strikingly, our data also revealed significant differences between ex vivo ATL tumor cells and in vitro HTLV-I cell lines. Specifically, miR-150 and miR-223 were up-regulated in ATL patients but consistently down-regulated in HTLV-I cell lines, suggesting that ATL cells and in vitro–established cells are derived from distinct cellular populations.

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Genistein induces apoptotic cell death associated with inhibition of the NF-κB pathway in adult T-cell leukemia cells

Cell Biology International ◽

10.1002/cbin.10101 ◽

2013 ◽

Vol 37 (7) ◽

pp. 742-747 ◽

Cited By ~ 12

Author(s):

Masao Yamasaki ◽

Yoshihiro Mine ◽

Misato Nishimura ◽

Satoshi Fujita ◽

Yoichi Sakakibara ◽

...

Keyword(s):

Cell Death ◽

T Cell ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Leukemia Cells ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia

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Interleukin-10 gene expression in adult T-cell leukemia

Blood ◽

10.1182/blood.v88.3.1035.bloodjournal8831035 ◽

1996 ◽

Vol 88 (3) ◽

pp. 1035-1045 ◽

Cited By ~ 55

Author(s):

N Mori ◽

PS Gill ◽

T Mougdil ◽

S Murakami ◽

S Eto ◽

...

Keyword(s):

Gene Expression ◽

T Cell ◽

Cell Lines ◽

Interleukin 10 ◽

Jurkat Cells ◽

Leukemic Cells ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Nf Kappa B ◽

Adult T Cell Leukemia

We studied the serum levels of interleukin-10 (IL-10), in patients with adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type I (HTLV-I) infection. Elevated IL-10 levels were observed in 33 of 45 patients with ATL. Fresh leukemic cells from ATL patients as well as HTLV-I-infected T-cell lines MT-2, SLB-1, and C10/MJ expressed IL-10 mRNA by reverse transcription-polymerase chain reaction analysis, whereas IL-10 mRNA was not detected in normal peripheral mononuclear cells and an uninfected T-cell line Jurkat. IL-10 protein was also detected in the culture medium of leukemic cells from ATL patients as well as these HTLV-I-infected cell lines, and in the extracellular fluids of ATL patients. Interestingly, MT-4 cells, which did not express Tax although transformed by HTLV-I, did not express IL-10 at either the mRNA or protein level. To elucidate the role of the HTLV-I encoded transactivator Tax in IL-10 gene expression, Jurkat cells were transfected with a Tax expression plasmid. In transiently transfected Jurkat cells, endogenous IL-10 mRNA expression was induced by Tax. Stably transfected Jurkat cell lines expressed IL-10 mRNA and secreted IL-10 protein into the culture medium. The nuclear factor (NF)-kappa B pathway is a target for Tax transactivation. We treated MT-2 cells with phosphorothioate antisense oligonucleotides to the p65 subunit of NF- kappa B. A reduction in the expression of p65 was accompanied by a reduction in IL-10 gene expression and IL-10 production. We showed that the IL-10 kappa B-like sites ( kappa B1,-2,034 to -2,025; kappa B2, - 1,961 to -1,952; kappa B3, -452 to -443) specifically formed a complex with NF-kappa B-containing nuclear extract from MT-2 cells and that NF- kappa B bound with the highest affinity to the kappa B2 element (kappa B2 > kappa B3 > kappa B1). These data suggest a general role for NF- kappa B activation in the induction of IL-10 gene transcription. Activation of IL-10 in HTLV-I-infected cells may contribute to the pathology associated with HTLV-I infection.

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Failure of regulation of Tac antigen/TCGF receptor on adult T-cell leukemia cells by anti-Tac monoclonal antibody

Blood ◽

10.1182/blood.v61.5.1014.bloodjournal6151014 ◽

1983 ◽

Vol 61 (5) ◽

pp. 1014-1016

Author(s):

M Tsudo ◽

T Uchiyama ◽

H Uchino ◽

J Yodoi

Keyword(s):

Monoclonal Antibody ◽

T Cells ◽

T Cell ◽

Cell Lines ◽

Leukemic Cells ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Down Regulation ◽

Adult T Cell Leukemia ◽

T Cell Lines

Anti-Tac monoclonal antibody, which blocks the membrane binding and action of human T-cell growth factor (TCGF), is strongly proposed to recognize TCGF receptor. We have demonstrated that anti-Tac antibody reacted with leukemic cells from patients with adult T-cell leukemia (ATL) and reacted with T-cell lines established from ATL cells. Although antigenic modulation, or down-regulation, of Tac antigen on activated normal T cells was induced by anti-Tac antibody, the expression of Tac antigen on ATL cells or T-cell lines was not affected when examined by the fluorescence-activated cell sorter (FACS) and the radioassay using 125I-staphylococcal protein A. These results indicate that regulation of Tac antigen-TCGF receptor is different between normal and malignant T cells, suggesting that failure of down- regulation of Tac antigen on leukemic cells by anti-Tac antibody may play an important role in the malignant proliferation of ATL cells.

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Induction of Apoptosis and Autophagy By Nampt Inhibition in Adult T-Cell Leukemia/Lymphoma and Leukemic Cell Lines

Blood ◽

10.1182/blood.v128.22.2327.2327 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2327-2327

Author(s):

Tomohiro Kozako ◽

Makoto Yoshimitsu ◽

Naomichi Arima ◽

Keisuke Sato ◽

Moe Toyoshima ◽

...

Keyword(s):

Cell Death ◽

T Cell ◽

Cell Lines ◽

Cell Lymphoma ◽

Leukemic Cell ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

Protein Levels ◽

Leukemic Cell Lines

Abstract Introduction: Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T-cell neoplasm that develops after long-term infection with human T-cell leukemia virus type I (HTLV-1). Despite the recent advances in chemotherapy, allogeneic hematopoietic stem cell transplantation, and supportive care, the prognosis for patients with acute, lymphoma, or unfavorable chronic subtypes is one of the poorest among hematological malignancies. The identification of new molecular targets for ATL prevention and treatment is desired. SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent histone/protein deacetylase, plays crucial roles in various physiological processes, including aging and apoptosis. We previously reported that ATL patients had significantly higher SIRT1 protein levels and novel small-molecule SIRT1 inhibitors are highly effective against ATL cells.1,2 Nicotinamide phosphoribosyltransferase (Nampt) also known as pre-B-cell colony-enhancing factor 1 or visfatin is a rate-limiting enzyme in NAD+ biosynthesis, and it regulates intracellular ATP levels in mammalian cells. Most cancer cells (acute myeloid leukemia [AML], acute lymphoblastic leukemia [ALL], mantle cell lymphoma [MCL], chronic lymphocytic leukemia [CLL], and T-cell lymphoma) is sensitive to low concentrations of FK866, Nampt inhibitor, as measured in cytotoxicity and clonogenic assays.3Here, we assessed how Nampt is regulated in ATL cells and leukemic cell lines. Results: We observed that ATL patients had significantly higher SIRT1 and Nampt protein levels than healthy controls. FK866 induced significant growth inhibition and apoptosis (Annexin V+ cells and TUNEL) in leukemia/lymphoma cell lines (HTLV-1-related cell lines: S1T, MT-2; Jurkat and HL60). FK866 showed potent activities with GI50values of 0.63, 3.7, 1.0, and 3,4 nM for S1T, MT-2, Jurkat, and HL60 cells, respectively. FK866 also activated caspase activity (caspase-3, 8, and 9) with DNA fragmentation. However, a caspase inhibitor did not inhibit this caspase-dependent cell death. Interestingly, FK866 increased the LC3-II-enriched protein fraction, indicating autophagosome accumulation as well as autophagy. Autophagy detection was also performed using the CytoID Autophagy detection kit. Autophagy levels are increased in the presence of STF-62247 pre-treated with bafilomycin A1, a specific inhibitor of vacuolar proton ATPase, whose inhibition is known to block the fusion of autophagosomes with lysosomes for 2 h. Thus, FK866 simultaneously caused apoptosis and autophagy. Conclusion:These results suggest that Nampt inhibitor is highly effective against ATL cells in caspase-dependent or -independent manners with autophagy, and that its clinical application might improve the prognosis of patients with this fatal disease. 1. Kozako T, Aikawa A, Shoji T, et al. High expression of the longevity gene product SIRT1 and apoptosis induction by sirtinol in adult T-cell leukemia cells. Int J Cancer. 2012;131:2044-2055. 2. Kozako T, Suzuki T, Yoshimitsu M, et al. Novel small-molecule SIRT1 inhibitors induce cell death in adult T-cell leukaemia cells. Sci Rep. 2015;5:11345. 3. Nahimana A, Attinger A, Aubry D, et al. The NAD biosynthesis inhibitor APO866 has potent antitumor activity against hematologic malignancies. Blood. 2009;113:3276-3286. Disclosures Yoshimitsu: HUYA Bioscience International: Research Funding.

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