Abstract

Adult T cell leukemia/lymphoma (ATL) is a peripheral T cell neoplasm of largely unknown genetic basis, associated with human T cell leukemia virus type-1 (HTLV-1) infection. Here we describe an integrated molecular study in which we performed whole-genome, exome, transcriptome and targeted resequencing, as well as array-based copy number and methylation analyses, in a total of 426 ATL cases. The identified alterations overlap significantly with the HTLV-1 Tax interactome and are highly enriched for T cell receptor–NF-κB signaling, T cell trafficking and other T cell–related pathways as well as immunosurveillance. Other notable features include a predominance of activating mutations (in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7) and gene fusions (CTLA4-CD28 and ICOS-CD28). We also discovered frequent intragenic deletions involving IKZF2, CARD11 and TP73 and mutations in GATA3, HNRNPA2B1, GPR183, CSNK2A1, CSNK2B and CSNK1A1. Our findings not only provide unique insights into key molecules in T cell signaling but will also guide the development of new diagnostics and therapeutics in this intractable tumor.

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References

  1. 1.

    & Human T-cell leukaemia virus type I and adult T-cell leukaemia-lymphoma. Lancet Oncol. 15, e517–e526 (2014).

  2. 2.

    & Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation. Nat. Rev. Cancer 7, 270–280 (2007).

  3. 3.

    & Molecular hallmarks of adult T cell leukemia. Front. Microbiol. 3, 334 (2012).

  4. 4.

    et al. Gain-of-function CCR4 mutations in adult T cell leukemia/lymphoma. J. Exp. Med. 211, 2497–2505 (2014).

  5. 5.

    , & WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (IARC Press, 2008).

  6. 6.

    & The APOBEC3 cytidine deaminases: an innate defensive network opposing exogenous retroviruses and endogenous retroelements. Annu. Rev. Immunol. 26, 317–353 (2008).

  7. 7.

    et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481, 157–163 (2012).

  8. 8.

    Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368, 2059–2074 (2013).

  9. 9.

    et al. The HTLV-1 Tax interactome. Retrovirology 5, 76 (2008).

  10. 10.

    , , & Antigen receptor signaling to NF-κB via CARMA1, BCL10, and MALT1. Cold Spring Harb. Perspect. Biol. 2, a003004 (2010).

  11. 11.

    & Regulation and function of NF-κB transcription factors in the immune system. Annu. Rev. Immunol. 27, 693–733 (2009).

  12. 12.

    & A new look at T cell receptor signaling to nuclear factor–κB. Trends Immunol. 34, 269–281 (2013).

  13. 13.

    & Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 13, 227–242 (2013).

  14. 14.

    et al. Casein kinase 1α governs antigen-receptor-induced NF-κB activation and human lymphoma cell survival. Nature 458, 92–96 (2009).

  15. 15.

    , , , & Crosstalk between the NF-κB activating IKK-complex and the CSN signalosome. J. Cell. Mol. Med. 14, 1555–1568 (2010).

  16. 16.

    , , , & Identification of phospholipase C γ1 as a protein tyrosine phosphatase μ substrate that regulates cell migration. J. Cell. Biochem. 112, 39–48 (2011).

  17. 17.

    , & Inhibitors of glycoprotein processing alter T-cell proliferative responses to antigen and to interleukin 2. Proc. Natl. Acad. Sci. USA 85, 5644–5648 (1988).

  18. 18.

    et al. The tumor suppressor gene WWOX links the canonical and noncanonical NF-κB pathways in HTLV-I Tax-mediated tumorigenesis. Blood 117, 1652–1661 (2011).

  19. 19.

    , , & Dysfunction of phospholipase Cγ in immune disorders and cancer. Trends Biochem. Sci. 39, 603–611 (2014).

  20. 20.

    et al. Cancer-associated protein kinase C mutations reveal kinase's role as tumor suppressor. Cell 160, 489–502 (2015).

  21. 21.

    , , , & Crystal structure and allosteric activation of protein kinase C βII. Cell 144, 55–66 (2011).

  22. 22.

    , & Pathogenesis of human B cell lymphomas. Annu. Rev. Immunol. 30, 565–610 (2012).

  23. 23.

    et al. Phosphorylation of the CARMA1 linker controls NF-κB activation. Immunity 23, 561–574 (2005).

  24. 24.

    et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat. Genet. 46, 166–170 (2014).

  25. 25.

    Regulatory and signaling properties of the Vav family. Mol. Cell. Biol. 20, 1461–1477 (2000).

  26. 26.

    , & CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol. Rev. 229, 12–26 (2009).

  27. 27.

    , & Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu. Rev. Immunol. 32, 659–702 (2014).

  28. 28.

    & Cellular immune response to HTLV-1. Oncogene 24, 6035–6046 (2005).

  29. 29.

    & Cellular and molecular mechanisms in cancer immune escape: a comprehensive review. Expert Rev. Clin. Immunol. 10, 41–62 (2014).

  30. 30.

    et al. Adult T-cell leukemia cells are characterized by abnormalities of Helios expression that promote T cell growth. Cancer Sci. 104, 1097–1106 (2013).

  31. 31.

    et al. Expression of a non-DNA-binding isoform of Helios induces T-cell lymphoma in mice. Blood 109, 2190–2197 (2007).

  32. 32.

    , & p73: friend or foe in tumorigenesis. Nat. Rev. Cancer 2, 605–615 (2002).

  33. 33.

    , , , & Synonymous mutations frequently act as driver mutations in human cancers. Cell 156, 1324–1335 (2014).

  34. 34.

    & Endogenous viruses: insights into viral evolution and impact on host biology. Nat. Rev. Genet. 13, 283–296 (2012).

  35. 35.

    et al. C2H2 zinc finger proteins greatly expand the human regulatory lexicon. Nat. Biotechnol. 33, 555–562 (2015).

  36. 36.

    , & Crosstalk in NF-κB signaling pathways. Nat. Immunol. 12, 695–708 (2011).

  37. 37.

    et al. Ataxin-1 and Brother of ataxin-1 are components of the Notch signalling pathway. EMBO Rep. 12, 428–435 (2011).

  38. 38.

    et al. Deletion of the RNA-binding proteins ZFP36L1 and ZFP36L2 leads to perturbed thymic development and T lymphoblastic leukemia. Nat. Immunol. 11, 717–724 (2010).

  39. 39.

    Protein kinase CK2: structure, regulation and role in cellular decisions of life and death. Biochem. J. 369, 1–15 (2003).

  40. 40.

    , , , & A corepressor/coactivator exchange complex required for transcriptional activation by nuclear receptors and other regulated transcription factors. Cell 116, 511–526 (2004).

  41. 41.

    & Identification of novel co-repressor molecules for Interferon Regulatory Factor-2. Nucleic Acids Res. 31, 3016–3026 (2003).

  42. 42.

    , & Splicing in oncogenesis and tumor suppression. Cancer Sci. 103, 1611–1616 (2012).

  43. 43.

    et al. Signal- and development-dependent alternative splicing of LEF1 in T cells is controlled by CELF2. Mol. Cell. Biol. 31, 2184–2195 (2011).

  44. 44.

    et al. POT1 mutations cause telomere dysfunction in chronic lymphocytic leukemia. Nat. Genet. 45, 526–530 (2013).

  45. 45.

    & Cancer genetics and epigenetics: two sides of the same coin? Cancer Cell 22, 9–20 (2012).

  46. 46.

    et al. Involvement of double-stranded RNA-dependent protein kinase and antisense viral RNA in the constitutive NFκB activation in adult T-cell leukemia/lymphoma cells. Leukemia 29, 1425–1429 (2015).

  47. 47.

    & Targeting the protein kinase C family: are we there yet? Nat. Rev. Cancer 7, 554–562 (2007).

  48. 48.

    et al. Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma: a proposal from an international consensus meeting. J. Clin. Oncol. 27, 453–459 (2009).

  49. 49.

    et al. Human T-cell leukemia virus type I (HTLV-1) proviral load and disease progression in asymptomatic HTLV-1 carriers: a nationwide prospective study in Japan. Blood 116, 1211–1219 (2010).

  50. 50.

    et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 478, 64–69 (2011).

  51. 51.

    et al. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat. Genet. 45, 860–867 (2013).

  52. 52.

    et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005).

  53. 53.

    et al. A robust algorithm for copy number detection using high-density oligonucleotide single nucleotide polymorphism genotyping arrays. Cancer Res. 65, 6071–6079 (2005).

  54. 54.

    et al. Highly sensitive method for genomewide detection of allelic composition in nonpaired, primary tumor specimens by use of Affymetrix single-nucleotide-polymorphism genotyping microarrays. Am. J. Hum. Genet. 81, 114–126 (2007).

  55. 55.

    et al. Allele-specific copy number analysis of tumors. Proc. Natl. Acad. Sci. USA 107, 16910–16915 (2010).

  56. 56.

    et al. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 12, R41 (2011).

  57. 57.

    et al. An empirical Bayesian framework for somatic mutation detection from cancer genome sequencing data. Nucleic Acids Res. 41, e89 (2013).

  58. 58.

    et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia 28, 241–247 (2014).

  59. 59.

    et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).

  60. 60.

    , , , & Quantitative reconstruction of leukocyte subsets using DNA methylation. Genome Biol. 15, R50 (2014).

  61. 61.

    et al. A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450 k DNA methylation data. Bioinformatics 29, 189–196 (2013).

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Acknowledgements

We thank S. Sakaguchi for expert opinion and M. Sago, M. Nakamura, H. Higashi, Y. Ogino, Y. Mori and S. Baba for technical assistance. This work was supported by Grants-in-Aid from the Ministry of Health, Labour and Welfare of Japan and the Japanese Agency for Medical Research and Development (Health and Labour Sciences Research Expenses for Commission and Applied Research for Innovative Treatment of Cancer), Japanese Society for the Promotion of Science (JSPS) KAKENHI (22134006), National Cancer Center Research and Development Funds (26-A-6) and the Funding Program for World-Leading Innovative Research and Development on Science and Technology (FIRST). The National Cancer Center Biobank was supported by the National Cancer Center Research and Development Fund, Japan. This research used computational resources of the K computer provided by the RIKEN Advanced Institute for Computational Science through the HPCI System Research project (hp140230). Supercomputing resources were also provided by the Human Genome Center, the Institute of Medical Science, The University of Tokyo.

Author information

Author notes

    • Yasunobu Nagata
    • , Akira Kitanaka
    • , Yuichi Shiraishi
    • , Teppei Shimamura
    • , Jun-ichirou Yasunaga
    •  & Yasushi Totoki

    These authors contributed equally to this work.

    • Kazuya Shimoda
    •  & Seishi Ogawa

    These authors jointly supervised this work.

Affiliations

  1. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

    • Keisuke Kataoka
    • , Yasunobu Nagata
    • , Aiko Sato-Otsubo
    • , Shinichi Kotani
    • , Yosaku Watatani
    • , June Takeda
    • , Masashi Sanada
    • , Hiromichi Suzuki
    • , Yusuke Sato
    • , Yusuke Shiozawa
    • , Tetsuichi Yoshizato
    • , Kenichi Yoshida
    • , Hideki Makishima
    •  & Seishi Ogawa
  2. Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.

    • Akira Kitanaka
    • , Kotaro Shide
    • , Yoko Kubuki
    • , Tomonori Hidaka
    • , Takuro Kameda
    •  & Kazuya Shimoda
  3. Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

    • Yuichi Shiraishi
    • , Kenichi Chiba
    • , Hiroko Tanaka
    •  & Satoru Miyano
  4. Division of Systems Biology, Center for Neurological Disease and Cancer, Graduate School of Medicine, Nagoya University, Nagoya, Japan.

    • Teppei Shimamura
  5. Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.

    • Jun-ichirou Yasunaga
    • , Guangyong Ma
    •  & Masao Matsuoka
  6. Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.

    • Yasushi Totoki
    • , Hiromi Nakamura
    • , Natsuko Hama
    •  & Tatsuhiro Shibata
  7. Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.

    • Genta Nagae
    •  & Hiroyuki Aburatani
  8. Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan.

    • Ryohei Ishii
    •  & Osamu Nureki
  9. Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.

    • Satsuki Muto
    •  & Toshiki Watanabe
  10. Department of Advanced Diagnosis, Clinical Research Center, Nagoya Medical Center, Nagoya, Japan.

    • Masashi Sanada
  11. Department of Frontier Life Science, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan.

    • Masako Iwanaga
  12. Department of Hematology, Kumamoto University School of Medicine, Kumamoto, Japan.

    • Kisato Nosaka
  13. Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

    • Masakatsu Hishizawa
    •  & Akifumi Takaori-Kondo
  14. Department of Hematology, Sasebo City General Hospital, Sasebo, Japan.

    • Hidehiro Itonaga
  15. Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.

    • Yoshitaka Imaizumi
    •  & Yasushi Miyazaki
  16. Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.

    • Wataru Munakata
    •  & Kensei Tobinai
  17. KAN Research Institute, Inc., Kobe, Japan.

    • Hideaki Ogasawara
    • , Toshitaka Sato
    • , Ken Sasai
    •  & Kenzo Muramoto
  18. Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

    • Marina Penova
    • , Takahisa Kawaguchi
    •  & Fumihiko Matsuda
  19. Division of Hematology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.

    • Tsuyoshi Nakamaki
  20. Department of Hematology and Oncology, Kanazawa University Hospital, Kanazawa, Japan.

    • Ken Ishiyama
  21. Division of Hematology, Department of Internal Medicine, Tokyo Metropolitan Ohtsuka Hospital, Tokyo, Japan.

    • Shuichi Miyawaki
  22. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

    • Sung-Soo Yoon
  23. Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.

    • Kengo Takeuchi
  24. Laboratory of Molecular Medicine, Human Genome Center, The institute of Medical Science, The University of Tokyo, Tokyo, Japan.

    • Tatsuhiro Shibata

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Contributions

Y. Shiraishi, K.C., H.T. and S. Miyano developed bioinformatics pipelines. K.K., Y.N., Y.T., H.S., Y. Shiozawa, T.Y., H.N., N.H. and T. Shibata performed sequencing data analyses. K.K., Y.N., S.K., Y.W., J.T. and K.Y. performed sequencing experiments. K.K., A.S.-O., S. Muto, Y. Sato, M.P., T. Kawaguchi and F.M. performed SNP array analysis. K.K., T. Shimamura, G.N. and H.A. performed methylation analysis. K.K., J.Y., R.I., G.M., H.O., T. Sato, K. Sasai, K.M., K. Takeuchi, O.N. and M.M. performed functional assays. K.K., M.S., H.M. and S.O. interpreted the results. A.K., J.Y., K.N., M.I., M.H., H.I., Y.I., W.M., K. Shide, Y.K., T.H., T. Kameda, T.N., K.I., S. Miyawaki, S.-S.Y., K. Tobinai, Y.M., A.T.-K., T.W., M.M. and K. Shimoda collected specimens. K.K. and S.O. generated figures and tables and wrote the manuscript. K. Shimoda and S.O. co-led the entire project. All authors participated in discussions and interpretation of the data and results.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Seishi Ogawa.

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DOI

https://doi.org/10.1038/ng.3415

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