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International Journal of Hematology

, Volume 105, Issue 4, pp 465–469 | Cite as

BCL6 locus is hypermethylated in angioimmunoblastic T-cell lymphoma

  • Shoko Nishizawa
  • Mamiko Sakata-Yanagimoto
  • Keiichiro Hattori
  • Hideharu Muto
  • Tran Nguyen
  • Koji Izutsu
  • Kenichi Yoshida
  • Seishi Ogawa
  • Naoya Nakamura
  • Shigeru Chiba
Original Article

Abstract

BCL6, a master transcription factor for differentiation of follicular helper T (TFH) cells, is highly expressed in angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphomas (PTCL) containing tumor cells with TFH features. TET2, encoding an epigenetic regulator, is frequently mutated in AITL/PTCL. We previously reported that Tet2 knockdown mice developed T-cell lymphomas with TFH features. Hypermethylation of the Bcl6 locus followed by BCL6 upregulation was thought to be the key event for lymphoma development in mice. The mechanisms by which BCL6 expression is upregulated in human AITL/PTCL, however, have not been elucidated. Here, we investigated the impact of TET2 mutations on methylation of BCL6 locus in human AITL/PTCL samples. Hypermethylation of the BCL6 locus was more frequent in PTCL samples than B-cell lymphoma samples (PTCL vs B-cell lymphomas: 9/42 vs 0/35). PTCL samples with TET2 mutations were more frequently hypermethylated than those without TET2 mutations (PTCL with TET2 mutations vs without mutations: 6/22 vs 0/17). BCL6 expression in hypermethylated samples was higher than that in low methylated samples. Deregulated BCL6 expression caused by hypermethylation and TET2 mutations may result in skewed TFH differentiation and eventually contribute to AITL/PTCL development in patients, as well as lymphoma development in Tet2 knockdown mice.

Keywords

Angioimmunoblastic T-cell lymphoma BCL6 expression Follicular helper T cells Hypermethylation TET2 mutation 

Notes

Acknowledgements

This work was supported by the Grants-in-Aid for Scientific Research (KAKENHI: 16K15497 to M. S.-Y.; and 24390241, 25112703, and 15H01504 to S. C.) from the Ministry of Education, Culture, Sports, and Science of Japan. This work was also supported by Research Grants from the Daiichi Sankyo Foundation of Life Science and the Naito Foundation to M.S.-Y.; and The Uehara Memorial Foundation, Leukemia Research Fund, Takeda Science Foundation, and Kobayashi Foundation for Cancer Research to S.C.

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References

  1. 1.
    de Leval L, Gisselbrecht C, Gaulard P. Advances in the understanding and management of angioimmunoblastic T-cell lymphoma. Br J Haematol. 2010;148(5):673–89.CrossRefPubMedGoogle Scholar
  2. 2.
    Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, Matskevitch TD, et al. Bcl6 mediates the development of T follicular helper cells. Science. 2009;325(5943):1001–5.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Bunting KL, Melnick AM. New effector functions and regulatory mechanisms of BCL6 in normal and malignant lymphocytes. Curr Opin Immunol. 2013;25(3):339–46.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Rodriguez-Pinilla SM, Atienza L, Murillo C, Perez-Rodriguez A, Montes-Moreno S, Roncador G, et al. Peripheral T-cell lymphoma with follicular T-cell markers. Am J Surg Pathol. 2008;32(12):1787–99.CrossRefPubMedGoogle Scholar
  5. 5.
    Lemonnier F, Couronne L, Parrens M, Jais JP, Travert M, Lamant L, et al. Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters. Blood. 2012;120(7):1466–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375–90.CrossRefPubMedGoogle Scholar
  7. 7.
    Sakata-Yanagimoto M, Enami T, Yoshida K, Shiraishi Y, Ishii R, Miyake Y, et al. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat Genet. 2014;46(2):171–5.CrossRefPubMedGoogle Scholar
  8. 8.
    Palomero T, Couronne L, Khiabanian H, Kim MY, Ambesi-Impiombato A, Perez-Garcia A, et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet. 2014;46(2):166–70.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Yoo HY, Sung MK, Lee SH, Kim S, Lee H, Park S, et al. A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma. Nat Genet. 2014;46(4):371–5.CrossRefPubMedGoogle Scholar
  10. 10.
    Ko M, An J, Rao A. DNA methylation and hydroxymethylation in hematologic differentiation and transformation. Curr Opin Cell Biol. 2015;37:91–101.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Wang C, McKeithan TW, Gong Q, Zhang W, Bouska A, Rosenwald A, et al. IDH2R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma. Blood. 2015;126(15):1741–52.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Muto H, Sakata-Yanagimoto M, Nagae G, Shiozawa Y, Miyake Y, Yoshida K, et al. Reduced TET2 function leads to T-cell lymphoma with follicular helper T-cell-like features in mice. Blood Cancer J. 2014;12(4):e264.CrossRefGoogle Scholar
  13. 13.
    Nguyen TB, Sakata-Yanagimoto M, Nakamoto-Matsubara R, Enami T, Ito Y, Kobayashi T, et al. Double somatic mosaic mutations in TET2 and DNMT3A–origin of peripheral T cell lymphoma in a case. Ann Hematol. 2015;94(7):1221–3.CrossRefPubMedGoogle Scholar
  14. 14.
    Basso K, Dalla-Favera R. Roles of BCL6 in normal and transformed germinal center B cells. Immunol Rev. 2012;247(1):172–83.CrossRefPubMedGoogle Scholar
  15. 15.
    Lu Z, Tsai AG, Akasaka T, Ohno H, Jiang Y, Melnick AM, et al. BCL6 breaks occur at different AID sequence motifs in Ig-BCL6 and non-Ig-BCL6 rearrangements. Blood. 2013;121(22):4551–4.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Green MR, Vicente-Duenas C, Romero-Camarero I, Long Liu C, Dai B, Gonzalez-Herrero I, et al. Transient expression of Bcl6 is sufficient for oncogenic function and induction of mature B-cell lymphoma. Nat Commun. 2014;2(5):3904.Google Scholar
  17. 17.
    Pasqualucci L, Migliazza A, Basso K, Houldsworth J, Chaganti RS, Dalla-Favera R. Mutations of the BCL6 proto-oncogene disrupt its negative autoregulation in diffuse large B-cell lymphoma. Blood. 2003;101(8):2914–23.CrossRefPubMedGoogle Scholar
  18. 18.
    Lai AY, Fatemi M, Dhasarathy A, Malone C, Sobol SE, Geigerman C, et al. DNA methylation revents CTCF-mediated silencing of the oncogene BCL6 in B cell lymphomas. J Exp Med. 2010;207(9):1939–50.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2016

Authors and Affiliations

  • Shoko Nishizawa
    • 1
  • Mamiko Sakata-Yanagimoto
    • 1
    • 2
    • 3
  • Keiichiro Hattori
    • 1
  • Hideharu Muto
    • 2
    • 3
  • Tran Nguyen
    • 1
  • Koji Izutsu
    • 4
    • 5
  • Kenichi Yoshida
    • 6
  • Seishi Ogawa
    • 6
  • Naoya Nakamura
    • 7
  • Shigeru Chiba
    • 1
    • 2
    • 3
  1. 1.Department of Hematology, Comprehensive Human, BiosciencesUniversity of TsukubaTsukubaJapan
  2. 2.Department of Hematology, Faculty of MedicineUniversity of TsukubaTsukubaJapan
  3. 3.Department of HematologyUniversity of Tsukuba HospitalTsukubaJapan
  4. 4.Department of HematologyToranomon HospitalTokyoJapan
  5. 5.Okinaka Memorial Institute for Medical ResearchTokyoJapan
  6. 6.Department of Pathology and Tumor BiologyGraduate School of Medicine, Kyoto UniversityKyotoJapan
  7. 7.Department of PathologyTokai University School of MedicineIseharaJapan

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