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

Cancer Gene Therapy volume 29, pages 1570–1577 (2022)Cite this article

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Abstract

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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Fig. 1: Expression of Ki-67 in PB-ATL cells from HTLV-1–infected individuals.
Fig. 2: Expression of Ki-67 in LN-ATL cells.
Fig. 3: Expression of Ki-67 in paired samples of PB and LNs from acute type patients.
Fig. 4: Kinetics of Ki-67 expression in CD4+ T-cells after anti-CD3 stimulation.
Fig. 5: Induction of T-cell quiescence regulators in PB-ATL cells.
Fig. 6: Expression of the hTERT gene and DNA methylation of its promoter in HTLV-1–infected cells.

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Acknowledgements

We thank A. Yamashita for critiquing the manuscript, C. Nagamine for providing technical assistance, and all the members of our laboratory for their suggestions and encouragement. This manuscript was supported by Grants-in-Aid for Scientific Research 19K08843 (M.M.) and JP23501258 (N.M.) from the Japan Society for the Promotion of Science and the Project of Establishing Medical Research Base Networks against Infectious Diseases in Okinawa (Y.T. and T.F.).

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Authors and Affiliations

  1. Department of Investigative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan

    Mariko Mizuguchi & Yoshiaki Takahashi

  2. Department of Pathology and Cell Biology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan

    Mitsuyoshi Takatori & Shugo Sakihama

  3. Human Gene Sciences Center, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

    Manami Yoshita-Takahashi & Masataka Nakamura

  4. Laboratory of Molecular Genetics, Graduate School of Health Sciences, University of the Ryukyus, Okinawa, Japan

    Naoki Imaizumi

  5. Department of Laboratory Medicine, Nagasaki University Hospital, Nagasaki, Japan

    Hiroo Hasegawa

  6. Department of Pathology and Laboratory Medicine, Graduate School of Medicine, Nagoya University, Nagoya, Japan

    Kennosuke Karube

  7. Laboratory of Hematoimmunology, Graduate School of Health Sciences, University of the Ryukyus, Okinawa, Japan

    Kennosuke Karube, Takuya Fukushima & Yuetsu Tanaka

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Contributions

MM, MN, and YTan conceived and designed the experiments; MM, MT, SS, MYT, and NI performed the experiments and analyzed the data; YTak, KK, TF, and YTan collected the samples and provided advice; HH provided HTLV-1–infected cell lines; MM, MN, and YTan wrote the manuscript, and all the authors read and approved the final manuscript.

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Correspondence to Mariko Mizuguchi or Yuetsu Tanaka.

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Mizuguchi, M., Takatori, M., Sakihama, S. et al. Acute type adult T-cell leukemia cells proliferate in the lymph nodes rather than in peripheral blood. Cancer Gene Ther 29, 1570–1577 (2022). https://doi.org/10.1038/s41417-022-00475-0

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