Home LiteratureArticle Details
PMID: 26437031 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Integrated molecular analysis of adult T cell leukemia/lymphoma.

Nature genetics ·Vol. 47 ·No. 11 ·2015-11-00 ·Pages 1304-15

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

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.

MeSH Terms
Adult Amino Acid Sequence DNA Copy Number Variations DNA Methylation Exome/genetics Gene Products, tax/genetics Genome, Human/genetics HEK293 Cells Host-Pathogen Interactions/genetics Human T-lymphotropic virus 1/genetics,physiology Humans Jurkat Cells Leukemia-Lymphoma, Adult T-Cell/genetics,virology Molecular Sequence Data Mutation Sequence Analysis, DNA/methods Sequence Homology, Amino Acid Signal Transduction/genetics Survival Analysis T-Lymphocytes/metabolism,virology Transcriptome/genetics
Chemicals
Gene Products, tax tax protein, Human T-lymphotrophic virus 1
Authors & Affiliations
59 authors, click to expand affiliations / ORCID
Kataoka Keisuke
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Nagata Yasunobu
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Kitanaka Akira
Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
Shiraishi Yuichi
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Shimamura Teppei
Division of Systems Biology, Center for Neurological Disease and Cancer, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
Yasunaga Jun-Ichirou
Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.
Totoki Yasushi
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
Chiba Kenichi
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Sato-Otsubo Aiko
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Nagae Genta
Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
Ishii Ryohei ORCID
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
Muto Satsuki
Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
Kotani Shinichi
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Watatani Yosaku
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Takeda June
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Sanada Masashi
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. | Department of Advanced Diagnosis, Clinical Research Center, Nagoya Medical Center, Nagoya, Japan.
Tanaka Hiroko
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Suzuki Hiromichi
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Sato Yusuke
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Shiozawa Yusuke
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Yoshizato Tetsuichi
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Yoshida Kenichi
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Makishima Hideki
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Iwanaga Masako
Department of Frontier Life Science, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan.
Ma Guangyong
Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.
Nosaka Kisato
Department of Hematology, Kumamoto University School of Medicine, Kumamoto, Japan.
Hishizawa Masakatsu
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Itonaga Hidehiro
Department of Hematology, Sasebo City General Hospital, Sasebo, Japan.
Imaizumi Yoshitaka
Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
Munakata Wataru
Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.
Ogasawara Hideaki
KAN Research Institute, Inc., Kobe, Japan.
Sato Toshitaka
KAN Research Institute, Inc., Kobe, Japan.
Sasai Ken
KAN Research Institute, Inc., Kobe, Japan.
Muramoto Kenzo
KAN Research Institute, Inc., Kobe, Japan.
Penova Marina
Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Kawaguchi Takahisa
Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Nakamura Hiromi
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
Hama Natsuko
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
Shide Kotaro
Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
Kubuki Yoko
Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
Hidaka Tomonori
Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
Kameda Takuro
Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
Nakamaki Tsuyoshi
Division of Hematology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Ishiyama Ken
Department of Hematology and Oncology, Kanazawa University Hospital, Kanazawa, Japan.
Miyawaki Shuichi
Division of Hematology, Department of Internal Medicine, Tokyo Metropolitan Ohtsuka Hospital, Tokyo, Japan.
Yoon Sung-Soo
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
Tobinai Kensei ORCID
Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.
Miyazaki Yasushi
Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
Takaori-Kondo Akifumi ORCID
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Matsuda Fumihiko
Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Takeuchi Kengo
Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
Nureki Osamu
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
Aburatani Hiroyuki
Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
Watanabe Toshiki
Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
Shibata Tatsuhiro
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan. | Laboratory of Molecular Medicine, Human Genome Center, The institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Matsuoka Masao ORCID
Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.
Miyano Satoru
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Shimoda Kazuya
Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
Ogawa Seishi
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
References (60)
60 references, click to expand
  1. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.
    Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50 PMID: 16199517
  2. 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. 2015 Jun;29(6):1425-9 PMID: 25567137
  3. Targeting the protein kinase C family: are we there yet?
    Nat Rev Cancer. 2007 Jul;7(7):554-62 PMID: 17585335
  4. p73: Friend or foe in tumorigenesis.
    Nat Rev Cancer. 2002 Aug;2(8):605-15 PMID: 12154353
  5. Identification of phospholipase C gamma1 as a protein tyrosine phosphatase mu substrate that regulates cell migration.
    J Cell Biochem. 2011 Jan;112(1):39-48 PMID: 20506511
  6. Pathogenesis of human B cell lymphomas.
    Annu Rev Immunol. 2012;30:565-610 PMID: 22224767
  7. CD28 and CTLA-4 coreceptor expression and signal transduction.
    Immunol Rev. 2009 May;229(1):12-26 PMID: 19426212
  8. Crosstalk in NF-κB signaling pathways.
    Nat Immunol. 2011 Jul 19;12(8):695-708 PMID: 21772278
  9. Splicing in oncogenesis and tumor suppression.
    Cancer Sci. 2012 Sep;103(9):1611-6 PMID: 22691055
  10. Gain-of-function CCR4 mutations in adult T cell leukemia/lymphoma.
    J Exp Med. 2014 Dec 15;211(13):2497-505 PMID: 25488980
  11. An empirical Bayesian framework for somatic mutation detection from cancer genome sequencing data.
    Nucleic Acids Res. 2013 Apr;41(7):e89 PMID: 23471004
  12. A new look at T cell receptor signaling to nuclear factor-κB.
    Trends Immunol. 2013 Jun;34(6):269-81 PMID: 23474202
  13. The tumor suppressor gene WWOX links the canonical and noncanonical NF-κB pathways in HTLV-I Tax-mediated tumorigenesis.
    Blood. 2011 Feb 3;117(5):1652-61 PMID: 21115974
  14. Crosstalk between the NF-kappaB activating IKK-complex and the CSN signalosome.
    J Cell Mol Med. 2010 Jun;14(6B):1555-68 PMID: 19656241
  15. Dysfunction of phospholipase Cγ in immune disorders and cancer.
    Trends Biochem Sci. 2014 Dec;39(12):603-11 PMID: 25456276
  16. Crystal structure and allosteric activation of protein kinase C βII.
    Cell. 2011 Jan 7;144(1):55-66 PMID: 21215369
  17. 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. 2010 Aug 26;116(8):1211-9 PMID: 20448111
  18. Antigen receptor signaling to NF-kappaB via CARMA1, BCL10, and MALT1.
    Cold Spring Harb Perspect Biol. 2010 Sep;2(9):a003004 PMID: 20685844
  19. The HTLV-1 Tax interactome.
    Retrovirology. 2008 Aug 14;5:76 PMID: 18702816
  20. Chemokines and chemokine receptors: positioning cells for host defense and immunity.
    Annu Rev Immunol. 2014;32:659-702 PMID: 24655300
  21. Human T-cell leukaemia virus type I and adult T-cell leukaemia-lymphoma.
    Lancet Oncol. 2014 Oct;15(11):e517-26 PMID: 25281470
  22. Regulation and function of NF-kappaB transcription factors in the immune system.
    Annu Rev Immunol. 2009;27:693-733 PMID: 19302050
  23. Protein kinase CK2: structure, regulation and role in cellular decisions of life and death.
    Biochem J. 2003 Jan 1;369(Pt 1):1-15 PMID: 12396231
  24. Casein kinase 1alpha governs antigen-receptor-induced NF-kappaB activation and human lymphoma cell survival.
    Nature. 2009 Mar 5;458(7234):92-6 PMID: 19118383
  25. Adult T-cell leukemia cells are characterized by abnormalities of Helios expression that promote T cell growth.
    Cancer Sci. 2013 Aug;104(8):1097-106 PMID: 23600753
  26. Endogenous viruses: insights into viral evolution and impact on host biology.
    Nat Rev Genet. 2012 Mar 16;13(4):283-96 PMID: 22421730
  27. A corepressor/coactivator exchange complex required for transcriptional activation by nuclear receptors and other regulated transcription factors.
    Cell. 2004 Feb 20;116(4):511-26 PMID: 14980219
  28. Regulatory and signaling properties of the Vav family.
    Mol Cell Biol. 2000 Mar;20(5):1461-77 PMID: 10669724
  29. Phosphorylation of the CARMA1 linker controls NF-kappaB activation.
    Immunity. 2005 Dec;23 (6):561-74 PMID: 16356855
  30. Frequent pathway mutations of splicing machinery in myelodysplasia.
    Nature. 2011 Sep 11;478(7367):64-9 PMID: 21909114
  31. Quantitative reconstruction of leukocyte subsets using DNA methylation.
    Genome Biol. 2014 Mar 05;15(3):R50 PMID: 24598480
  32. Expression of a non-DNA-binding isoform of Helios induces T-cell lymphoma in mice.
    Blood. 2007 Mar 1;109(5):2190-7 PMID: 17110463
  33. Synonymous mutations frequently act as driver mutations in human cancers.
    Cell. 2014 Mar 13;156(6):1324-1335 PMID: 24630730
  34. Cellular and molecular mechanisms in cancer immune escape: a comprehensive review.
    Expert Rev Clin Immunol. 2014 Jan;10(1):41-62 PMID: 24325346
  35. Cancer-associated protein kinase C mutations reveal kinase's role as tumor suppressor.
    Cell. 2015 Jan 29;160(3):489-502 PMID: 25619690
  36. Inhibitors of glycoprotein processing alter T-cell proliferative responses to antigen and to interleukin 2.
    Proc Natl Acad Sci U S A. 1988 Aug;85(15):5644-8 PMID: 3135550
  37. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia.
    Nature. 2012 Jan 11;481(7380):157-63 PMID: 22237106
  38. Integrated molecular analysis of clear-cell renal cell carcinoma.
    Nat Genet. 2013 Aug;45(8):860-7 PMID: 23797736
  39. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers.
    Genome Biol. 2011;12(4):R41 PMID: 21527027
  40. Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation.
    Nat Rev Cancer. 2007 Apr;7(4):270-80 PMID: 17384582
  41. Molecular mechanisms of T cell co-stimulation and co-inhibition.
    Nat Rev Immunol. 2013 Apr;13(4):227-42 PMID: 23470321
  42. Ataxin-1 and Brother of ataxin-1 are components of the Notch signalling pathway.
    EMBO Rep. 2011 May;12(5):428-35 PMID: 21475249
  43. Mutational heterogeneity in cancer and the search for new cancer-associated genes.
    Nature. 2013 Jul 11;499(7457):214-218 PMID: 23770567
  44. Molecular hallmarks of adult T cell leukemia.
    Front Microbiol. 2012 Sep 17;3:334 PMID: 23060864
  45. A robust algorithm for copy number detection using high-density oligonucleotide single nucleotide polymorphism genotyping arrays.
    Cancer Res. 2005 Jul 15;65(14):6071-9 PMID: 16024607
  46. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes.
    Leukemia. 2014 Feb;28(2):241-7 PMID: 24220272
  47. C2H2 zinc finger proteins greatly expand the human regulatory lexicon.
    Nat Biotechnol. 2015 May;33(5):555-62 PMID: 25690854
  48. 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. 2007 Jul;81(1):114-26 PMID: 17564968
  49. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia.
    N Engl J Med. 2013 May 30;368(22):2059-74 PMID: 23634996
  50. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas.
    Nat Genet. 2014 Feb;46(2):166-70 PMID: 24413734
  51. Deletion of the RNA-binding proteins ZFP36L1 and ZFP36L2 leads to perturbed thymic development and T lymphoblastic leukemia.
    Nat Immunol. 2010 Aug;11(8):717-24 PMID: 20622884
  52. A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450 k DNA methylation data.
    Bioinformatics. 2013 Jan 15;29(2):189-96 PMID: 23175756
  53. Identification of novel co-repressor molecules for Interferon Regulatory Factor-2.
    Nucleic Acids Res. 2003 Jun 15;31(12):3016-26 PMID: 12799427
  54. Cancer genetics and epigenetics: two sides of the same coin?
    Cancer Cell. 2012 Jul 10;22(1):9-20 PMID: 22789535
  55. POT1 mutations cause telomere dysfunction in chronic lymphocytic leukemia.
    Nat Genet. 2013 May;45(5):526-30 PMID: 23502782
  56. The APOBEC3 cytidine deaminases: an innate defensive network opposing exogenous retroviruses and endogenous retroelements.
    Annu Rev Immunol. 2008;26:317-53 PMID: 18304004
  57. Signal- and development-dependent alternative splicing of LEF1 in T cells is controlled by CELF2.
    Mol Cell Biol. 2011 Jun;31(11):2184-95 PMID: 21444716
  58. Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma: a proposal from an international consensus meeting.
    J Clin Oncol. 2009 Jan 20;27(3):453-9 PMID: 19064971
  59. Cellular immune response to HTLV-1.
    Oncogene. 2005 Sep 5;24(39):6035-46 PMID: 16155610
  60. Allele-specific copy number analysis of tumors.
    Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16910-5 PMID: 20837533
Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.3415
Published
2015-11-00
Epub
2015-00-05
Pages
1304-15
Language
English
Region
United States
NLM ID
9216904
Subset
IM
Corrections
CommentIn
PMID: 26506901
External Links
PubMed source DOI: 10.1038/ng.3415 View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2