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• Acute type adult T-cell leukemia cells proliferate in the lymph nodes rather than in peripheral blood.

  Mizuguchi M, Takatori M, Sakihama S, Yoshita-Takahashi M, Imaizumi N, Takahashi Y, Hasegawa H, Karube K, Fukushima T, Nakamura M, Tanaka Y

  Cancer gene therapy ( Cancer Gene Therapy )  29 ( 11 ) 1570 - 1577   2022.04 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  A massive increase in the number of mature CD4+ T-cells in peripheral blood (PB) is a defining characteristic of acute type of adult T-cell leukemia (ATL). To date, the site of proliferation of ATL cells in the body has been unclear. In an attempt to address this question, we examined the expression of the proliferation marker, Ki-67, in freshly isolated ATL cells from PB and lymph nodes (LNs) of patients with various types of ATL. Our findings reveal that LN-ATL cells display higher expression of the Ki-67 antigen than PB-ATL cells in acute type patients. The gene expression of T-cell quiescence regulators such as Krüppel-like factor 2/6 and forkhead box protein 1 was substantially high in acute type PB-ATL cells. The expression of human telomerase reverse transcriptase, which is involved in T-cell expansion, was significantly low in PB-ATL cells from acute type patients, similar to that in normal resting T-cells. These findings suggest that ATL cells proliferate in the LNs rather than in PB.

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• Elevation of the Plasma Levels of TNF Receptor 2 in Association with Those of CD25, OX40, and IL-10 and HTLV-1 Proviral Load in Acute Adult T-Cell Leukemia.

  Kato M, Imaizumi N, Tanaka R, Mizuguchi M, Hayashi M, Miyagi T, Uchihara J, Ohshiro K, Todoroki J, Karube K, Masuzaki H, Tanaka Y, Fukushima T

  Viruses ( Viruses )  14 ( 4 ) 751 - 751   2022.04 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  Adult T-cell leukemia/lymphoma (ATL) cells express TNF receptor type-2 (TNFR2) on their surface and shed its soluble form (sTNFR2). We previously reported that sTNFR2 levels were highly elevated in the plasma of patients with acute ATL. To investigate whether its quantitation would be helpful for the diagnosis or prediction of the onset of acute ATL, we examined the plasma levels of sTNFR2 in a large number of specimens obtained from a cohort of ATL patients and asymptomatic human T-cell leukemia virus type 1 (HTLV-1) carriers (ACs) and compared them to those of other candidate ATL biomarkers (sCD25, sOX40, and IL-10) by enzyme-linked immunosorbent assays (ELISA) and HTLV-1 proviral loads. We observed that sTNFR2 levels were significantly elevated in acute ATL patients compared to ACs and patients with other types of ATL (chronic, smoldering, and lymphoma). Importantly, sTNFR2 levels were significantly correlated with those of sCD25, sOX40, and IL-10, as well as proviral loads. Thus, the present study confirmed that an increase in plasma sTNFR2 levels is a biomarker for the diagnosis of acute ATL. Examination of plasma sTNFR2 alone or in combination with other ATL biomarkers may be helpful for the diagnosis of acute ATL.

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• A protective role of HTLV-1 gp46-specific neutralizing and antibody-dependent cellular cytotoxicity-inducing antibodies in progression to adult T-cell leukemia (ATL).

  Tanaka Y, Tanaka R, Imaizumi N, Mizuguchi M, Takahashi Y, Hayashi M, Miyagi T, Uchihara J, Ohshiro K, Masuzaki H, Fukushima T

  Frontiers in immunology ( Frontiers in Immunology )  13   921606 - 921606   2022 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  Human T-cell leukemia virus type-1 (HTLV-1) establishes a long-term persistent infection in humans and causes malignant T-cell leukemia, adult T-cell leukemia (ATL). HTLV-1-specific cytotoxic T lymphocytes have been suggested to play a major role in the immunosurveillance of HTLV-1-infected T cells. However, it remains unclear whether HTLV-1-specific functional antibodies are also involved in the host defense. To explore the role of antibodies in the course of HTLV-1 infection, we quantitated HTLV-1-specific neutralizing and antibody-dependent cellular cytotoxicity (ADCC)-inducing antibody levels in plasma from asymptomatic carriers (ACs) and ATL patients. The levels of neutralizing antibodies, as determined by a syncytium inhibition assay, were significantly lower in acute and chronic ATL patients than in ACs. The levels of ADCC-inducing activity were tested using an autologous pair of HTLV-1-producing cells and cultured natural killer (NK) cells, which showed that the ADCC-inducing activity of IgG at a concentration of 100 µg/ml was comparable between ACs and acute ATL patients. The anti-gp46 antibody IgG levels, determined by ELISA, correlated with those of the neutralizing and ADCC-inducing antibodies. In contrast, the proviral loads did not correlate with any of these antibody levels. NK cells and a monoclonal anti-gp46 antibody reduced the number of HTLV-1 Tax-expressing cells in cultured peripheral blood mononuclear cells from patients with aggressive ATL. These results suggest a protective role for HTLV-1 neutralizing and ADCC-inducing antibodies during the course of HTLV-1 infection.

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• Promoter CpG methylation inhibits Krüppel-like factor 2 (KLF2)-Mediated repression of hTERT gene expression in human T-cells.

  Mizuguchi M, Hara T, Yoshita-Takahashi M, Kohda T, Tanaka Y, Nakamura M

  Biochemistry and biophysics reports ( Biochemistry and Biophysics Reports )  26   100984 - 100984   2021.07 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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• ER-resident sensor PERK is essential for mitochondrial thermogenesis in brown adipose tissue.

  Kato H, Okabe K, Miyake M, Hattori K, Fukaya T, Tanimoto K, Beini S, Mizuguchi M, Torii S, Arakawa S, Ono M, Saito Y, Sugiyama T, Funatsu T, Sato K, Shimizu S, Oyadomari S, Ichijo H, Kadowaki H, Nishitoh H

  Life science alliance ( Life Science Alliance )  3 ( 3 )   2020.03 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  Mitochondria play a central role in the function of brown adipocytes (BAs). Although mitochondrial biogenesis, which is indispensable for thermogenesis, is regulated by coordination between nuclear DNA transcription and mitochondrial DNA transcription, the molecular mechanisms of mitochondrial development during BA differentiation are largely unknown. Here, we show the importance of the ER-resident sensor PKR-like ER kinase (PERK) in the mitochondrial thermogenesis of brown adipose tissue. During BA differentiation, PERK is physiologically phosphorylated independently of the ER stress. This PERK phosphorylation induces transcriptional activation by GA-binding protein transcription factor α subunit (GABPα), which is required for mitochondrial inner membrane protein biogenesis, and this novel role of PERK is involved in maintaining the body temperatures of mice during cold exposure. Our findings demonstrate that mitochondrial development regulated by the PERK-GABPα axis is indispensable for thermogenesis in brown adipose tissue.

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Grant-in-Aid for Scientific Research 【 display / non-display 】

Grant-in-Aid for Scientific Research 【 display / non-display 】

• Grant-in-Aid for Scientific Research(C)

  Project Year: 2019.04  -  2022.03 

  Direct: 3,400,000 (YEN)  Overheads: 1,020,000 (YEN)  Total: 4,420,000 (YEN)

• Grant-in-Aid for Young Scientists(B)

  Project Year: 2017.04  -  2019.03 

  Direct: 2,800,000 (YEN)  Overheads: 840,000 (YEN)  Total: 3,640,000 (YEN)