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FX1, a BCL6 inhibitor, reactivates BCL6 target genes and suppresses HTLV-1-infected T cells

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Summary

Human T cell leukemia virus type 1 (HTLV-1) is responsible for adult T cell leukemia (ATL); however, molecular and cellular mechanisms underlying HTLV-1-induced leukemogenesis are unclear. BCL6 oncogene is involved in cancer progression and a preferred target of anti-cancer treatments. Here, we aimed to evaluate BCL6 expression and the effects of BCL6 inhibitor (FX1) on HTLV-1-infected T cell lines. BCL6 expression was higher in HTLV-1-infected T cell lines than that in uninfected T cell lines. BCL6 was localized mostly in the nucleus. The virus oncoprotein Tax induced BCL6 mRNA expression in T cells, whereas BCL6 knockdown reduced HTLV-1-infected T cell proliferation; thus, confirmed the association of BCL6 with cancer progression. Further, FX1 efficiently inhibited the cell growth and survival of HTLV-1-infected T cell lines in a dose- and time-dependent manner. The decreased levels of cell cycle regulatory proteins (phosphorylated retinoblastoma protein, cyclin-dependent kinase 4, cyclin D2 and c-Myc) and the increased levels of BCL6 target proteins (p21, p27 and p53) showed that FX1 arrested cell cycle at the G1 phase. Apoptosis was induced concomitantly with Bak upregulation and downregulation of survivin, Bcl-xL and Mcl-1, as well as with the activation of caspase-3, -8, -9 and poly(ADP-ribose) polymerase. FX1 also inhibited NF-κB and Akt signaling pathways. These events were because of the induction of the activity of cell cycle checkpoint proteins and relief of direct repression of the targets of cell cycle checkpoint proteins. Thus, BCL6 might be considered a novel target for ATL treatment.

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Data availability

The data and materials used in this study are available from the corresponding author on reasonable request.

References

  1. Iwanaga M, Watanabe T, Yamaguchi K (2012) Adult T-cell leukemia: a review of epidemiological evidence. Front Microbiol 3:322

    Article  CAS  Google Scholar 

  2. Nasr R, Marçais A, Hermine O, Bazarbachi A (2017) Overview of targeted therapies for adult T-cell leukemia/lymphoma. Methods Mol Biol 1582:197–216

    Article  CAS  Google Scholar 

  3. Ishitsuka K, Tamura K (2014) Human T-cell leukaemia virus type I and adult T-cell leukaemia-lymphoma. Lancet Oncol 15:e517–e526

    Article  CAS  Google Scholar 

  4. Matsuoka M (2005) Human T-cell leukemia virus type I (HTLV-I) infection and the onset of adult T-cell leukemia (ATL). Retrovirology 2:27

    Article  Google Scholar 

  5. Yamagishi M, Watanabe T (2012) Molecular hallmarks of adult T cell leukemia. Front Microbiol 3:334

    Article  CAS  Google Scholar 

  6. Mohanty S, Harhaj EW (2020) Mechanisms of oncogenesis by HTLV-1 Tax. Pathogens 9:543

    Article  CAS  Google Scholar 

  7. Cardenas MG, Oswald E, Yu W, Xue F, MacKerell AD Jr, Melnick AM (2017) The expanding role of the BCL6 oncoprotein as a cancer therapeutic target. Clin Cancer Res 23:885–893

    Article  CAS  Google Scholar 

  8. Li S, Wang Z, Lin L, Wu Z, Yu Q, Gao F, Zhang J, Xu Y (2019) BCL6 rearrangement indicates poor prognosis in diffuse large B-cell lymphoma patients: a meta-analysis of cohort studies. J Cancer 10:530–538

    Article  CAS  Google Scholar 

  9. Miyoshi I, Kubonishi I, Yoshimoto S, Akagi T, Ohtsuki Y, Shiraishi Y, Nagata K, Hinuma Y (1981) Type C virus particles in a cord T-cell line derived by co-cultivating normal human cord leukocytes and human leukaemic T cells. Nature 294:770–771

    Article  CAS  Google Scholar 

  10. Yamamoto N, Okada M, Koyanagi Y, Kannagi M, Hinuma Y (1982) Transformation of human leukocytes by cocultivation with an adult T cell leukemia virus producer cell line. Science 217:737–739

    Article  CAS  Google Scholar 

  11. Koeffler HP, Chen IS, Golde DW (1984) Characterization of a novel HTLV-infected cell line. Blood 64:482–490

    Article  CAS  Google Scholar 

  12. Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC (1980) Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci USA 77:7415–7419

    Article  CAS  Google Scholar 

  13. Miyoshi I, Kubonishi I, Sumida M, Hiraki S, Tsubota T, Kimura I, Miyamoto K, Sato J (1980) A novel T-cell line derived from adult T-cell leukemia. Gan 71:155–156

    CAS  PubMed  Google Scholar 

  14. Ohtani K, Nakamura M, Saito S, Nagata K, Sugamura K, Hinuma Y (1989) Electroporation: application to human lymphoid cell lines for stable introduction of a transactivator gene of human T-cell leukemia virus type I. Nucleic Acids Res 17:1589–1604

    Article  CAS  Google Scholar 

  15. Zhang C, Ao Z, Seth A, Schlossman SF (1996) A mitochondrial membrane protein defined by a novel monoclonal antibody is preferentially detected in apoptotic cells. J Immunol 157:3980–3987

    CAS  PubMed  Google Scholar 

  16. Tanaka Y, Yoshida A, Takayama Y, Tsujimoto H, Tsujimoto A, Hayami M, Tozawa H (1990) Heterogeneity of antigen molecules recognized by anti-tax1 monoclonal antibody Lt-4 in cell lines bearing human T cell leukemia virus type I and related retroviruses. Jpn J Cancer Res 81:225–231

    Article  CAS  Google Scholar 

  17. Mori N, Ishikawa C, Senba M (2015) Activation of PKC-δ in HTLV-1-infected T cells. Int J Oncol 46:1609–1618

    Article  CAS  Google Scholar 

  18. Kataoka K, Nagata Y, Kitanaka A, Shiraishi Y, Shimamura T, Yasunaga J, Totoki Y, Chiba K, Sato-Otsubo A, Nagae G, Ishii R, Muto S, Kotani S, Watatani Y, Takeda J, Sanada M, Tanaka H, Suzuki H, Sato Y, Shiozawa Y, Yoshizato T, Yoshida K, Makishima H, Iwanaga M, Ma G, Nosaka K, Hishizawa M, Itonaga H, Imaizumi Y, Munakata W, Ogasawara H, Sato T, Sasai K, Muramoto K, Penova M, Kawaguchi T, Nakamura H, Hama N, Shide K, Kubuki Y, Hidaka T, Kameda T, Nakamaki T, Ishiyama K, Miyawaki S, Yoon SS, Tobinai K, Miyazaki Y, Takaori-Kondo A, Matsuda F, Takeuchi K, Nureki O, Aburatani H, Watanabe T, Shibata T, Matsuoka M, Miyano S, Shimoda K, Ogawa S (2015) Integrated molecular analysis of adult T cell leukemia/lymphoma. Nat Genet 47:1304–1315

    Article  CAS  Google Scholar 

  19. Arguni E, Arima M, Tsuruoka N, Sakamoto A, Hatano M, Tokuhisa T (2006) JunD/AP-1 and STAT3 are the major enhancer molecules for high Bcl6 expression in germinal center B cells. Int Immunol 18:1079–1089

    Article  CAS  Google Scholar 

  20. Gazon H, Barbeau B, Mesnard JM, Peloponese JM Jr (2018) Hijacking of the AP-1 signaling pathway during development of ATL. Front Microbiol 8:2686

    Article  Google Scholar 

  21. Inoue J, Seiki M, Taniguchi T, Tsuru S, Yoshida M (1986) Induction of interleukin 2 receptor gene expression by p40x encoded by human T-cell leukemia virus type 1. EMBO J 5:2883–2888

    Article  CAS  Google Scholar 

  22. Cardenas MG, Yu W, Beguelin W, Teater MR, Geng H, Goldstein RL, Oswald E, Hatzi K, Yang SN, Cohen J, Shaknovich R, Vanommeslaeghe K, Cheng H, Liang D, Cho HJ, Abbott J, Tam W, Du W, Leonard JP, Elemento O, Cerchietti L, Cierpicki T, Xue F, MacKerell AD Jr, Melnick AM (2016) Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma. J Clin Invest 126:3351–3362

    Article  Google Scholar 

  23. Bretones G, Delgado MD, León J (2015) Myc and cell cycle control. Biochim Biophys Acta 1849:506–516

    Article  CAS  Google Scholar 

  24. Zheng H-C (2017) The molecular mechanisms of chemoresistance in cancers. Oncotarget 8:59950–59964

    Article  Google Scholar 

  25. Mori N (2009) Cell signaling modifiers for molecular targeted therapy in ATLL. Front Biosci 14:1479–1489

    Article  CAS  Google Scholar 

  26. Goldar S, Khaniani MS, Derakhshan SM, Baradaran B (2015) Molecular mechanisms of apoptosis and roles in cancer development and treatment. Asian Pac J Cancer Prev 16:2129–2144

    Article  Google Scholar 

  27. Hoffman B, Liebermann DA (2008) Apoptotic signaling by c-MYC. Oncogene 27:6462–6472

    Article  CAS  Google Scholar 

  28. Pahl HL (1999) Activators and target genes of Rel/NF-κB transcription factors. Oncogene 18:6853–6866

    Article  CAS  Google Scholar 

  29. Iwanaga R, Ohtani K, Hayashi T, Nakamura M (2001) Molecular mechanism of cell cycle progression induced by the oncogene product Tax of human T-cell leukemia virus type I. Oncogene 20:2055–2067

    Article  CAS  Google Scholar 

  30. Reuter S, Prasad S, Phromnoi K, Ravindran J, Sung B, Yadav VR, Kannappan R, Chaturvedi MM, Aggarwal BB (2010) Thiocolchicoside exhibits anticancer effects through downregulation of NF-κB pathway and its regulated gene products linked to inflammation and cancer. Cancer Prev Res 3:1462–1472

    Article  CAS  Google Scholar 

  31. Viatour P, Merville M-P, Bours V, Chariot A (2005) Phosphorylation of NF-κB and IκB proteins: implications in cancer and inflammation. Trends Biochem Sci 30:43–52

    Article  CAS  Google Scholar 

  32. Shao J, Fujiwara T, Kadowaki Y, Fukazawa T, Waku T, Itoshima T, Yamatsuji T, Nishizaki M, Roth JA, Tanaka N (2000) Overexpression of the wild-type p53 gene inhibits NF-κB activity and synergizes with aspirin to induce apoptosis in human colon cancer cells. Oncogene 19:726–736

    Article  CAS  Google Scholar 

  33. Kawauchi K, Araki K, Tobiume K, Tanaka N (2008) p53 regulates glucose metabolism through an IKK-NF-κB pathway and inhibits cell transformation. Nat Cell Biol 10:611–618

    Article  CAS  Google Scholar 

  34. Levine AJ, Puzio-Kuter AM (2010) The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 330:1340–1344

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge the Fujisaki Cell Center, Hayashibara Biochemical Laboratories, Inc. for providing HUT-102, MT-1 and Jurkat cells, Dr. Naoki Yamamoto (Tokyo Medical and Dental University) for providing MT-2, MT-4 and MOLT-4 cells, Dr. Masahiro Fujii (Niigata University) for providing CCRF-CEM cells, and Dr. Diane Prager (UCLA School of Medicine) for providing SLB-1 cells. Protein concentration measurement and flow cytometry analyses were performed at the University of the Ryukyus Center for Research Advancement and Collaboration. We thank Editage (www.editage.com) for their assistance with English language editing.

Funding

The study was supported in part by JSPS KAKENHI (17K07175).

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Authors and Affiliations

  1. Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan

    Chie Ishikawa & Naoki Mori

  2. Division of Health Sciences, Transdisciplinary Research Organization for Subtropics and Island Studies, University of the Ryukyus, 1 Senbaru, Nishihara, Okinawa, 903-0213, Japan

    Chie Ishikawa

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  1. Chie Ishikawa
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Contributions

Conceptualization: N.M.; methodology: C.I. and N.M.; formal analysis and investigation: C.I. and N.M.; writing-original draft preparation: C.I.; writing-reviewing and editing: N.M.; funding acquisition: C.I.; resources: N.M.; supervision: N.M.

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Ishikawa, C., Mori, N. FX1, a BCL6 inhibitor, reactivates BCL6 target genes and suppresses HTLV-1-infected T cells. Invest New Drugs 40, 245–254 (2022). https://doi.org/10.1007/s10637-021-01196-1

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