title: The role of HTLV-1 clonality, proviral structure, and genomic integration site in adult T-cell leukemia/lymphoma.
abstract: Adult T-cell leukemia/lymphoma (ATL) occurs in ∼5% of human T-lymphotropic virus type 1 (HTLV-1)-infected individuals and is conventionally thought to be a monoclonal disease in which a single HTLV-1(+) T-cell clone progressively outcompetes others and undergoes malignant transformation. Here, using a sensitive high-throughput method, we quantified clonality in 197 ATL cases, identified genomic characteristics of the proviral integration sites in malignant and nonmalignant clones, and investigated the proviral features (genomic structure and 5' long terminal repeat methylation) that determine its capacity to express the HTLV-1 oncoprotein Tax. Of the dominant, presumed malignant clones, 91% contained a single provirus. The genomic characteristics of the integration sites in the ATL clones resembled those of the frequent low-abundance clones (present in both ATL cases and carriers) and not those of the intermediate-abundance clones observed in 24% of ATL cases, suggesting that oligoclonal proliferation per se does not cause malignant transformation. Gene ontology analysis revealed an association in 6% of cases between ATL and integration near host genes in 3 functional categories, including genes previously implicated in hematologic malignancies. In all cases of HTLV-1 infection, regardless of ATL, there was evidence of preferential survival of the provirus in vivo in acrocentric chromosomes (13, 14, 15, 21, and 22).
authors.affiliation: Section of Immunology, Wright-Fleming Institute, Imperial College, London, United Kingdom;
authors.forename: Lucy B
authors.initials: LB
authors.lastname: Cook
authors.affiliation: Section of Immunology, Wright-Fleming Institute, Imperial College, London, United Kingdom;
authors.forename: Anat
authors.initials: A
authors.lastname: Melamed
authors.affiliation: Section of Immunology, Wright-Fleming Institute, Imperial College, London, United Kingdom;
authors.forename: Heather
authors.initials: H
authors.lastname: Niederer
authors.affiliation: Imperial Molecular Pathology Laboratory, Imperial College Healthcare NHS Trust and Academic Health Sciences Centre, Hammersmith Hospital, London, United Kingdom; Centre for Haematology, Faculty of Medicine, Imperial College, Hammersmith Hospital, London, United Kingdom;
authors.forename: Mikel
authors.initials: M
authors.lastname: Valganon
authors.affiliation: Section of Immunology, Wright-Fleming Institute, Imperial College, London, United Kingdom;
authors.forename: Daniel
authors.initials: D
authors.lastname: Laydon
authors.affiliation: Imperial Molecular Pathology Laboratory, Imperial College Healthcare NHS Trust and Academic Health Sciences Centre, Hammersmith Hospital, London, United Kingdom; Centre for Haematology, Faculty of Medicine, Imperial College, Hammersmith Hospital, London, United Kingdom;
authors.forename: Letizia
authors.initials: L
authors.lastname: Foroni
authors.affiliation: Section of Virology, Wright-Fleming Institute, Imperial College, London, United Kingdom; and.
authors.forename: Graham P
authors.initials: GP
authors.lastname: Taylor
authors.affiliation: Institute for Viral Research, Kyoto University, Kyoto, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Matsuoka
authors.affiliation: Section of Immunology, Wright-Fleming Institute, Imperial College, London, United Kingdom;
authors.forename: Charles R M
authors.initials: CR
authors.lastname: Bangham
mesh_terms: D000328:Adult; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D002874:Chromosome Mapping; D002999:Clone Cells / Q000378:metabolism / Q000821:virology; D015331:Cohort Studies; D015870:Gene Expression; D063990:Gene Ontology; D016356:Gene Products, tax / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D015490:HTLV-I Infections / Q000235:genetics* / Q000821:virology; D054884:Host-Pathogen Interactions / Q000235:genetics; D015368:Human T-lymphotropic virus 1 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000821:virology; D011533:Proviruses / Q000235:genetics*; D051381:Rats; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D020079:Terminal Repeat Sequences / Q000235:genetics; D016662:Virus Integration / Q000235:genetics*
chemical_list: D016356:Gene Products, tax; C514970:tax protein, Human T-lymphotrophic virus 1
references.citation: Br J Haematol. 1991 Nov;79(3):428-37
references.pmid: 1751370
references.citation: PLoS Pathog. 2010 Sep 23;6(9):e1001117
references.pmid: 20886101
references.citation: Blood. 2012 Oct 25;120(17):3488-90
references.pmid: 22955925
references.citation: Blood. 1988 Oct;72(4):1117-23
references.pmid: 3167199
references.citation: Int J Cancer. 2004 Apr 20;109(4):559-67
references.pmid: 14991578
references.citation: Blood. 1997 Feb 1;89(3):948-56
references.pmid: 9028326
references.citation: Nat Rev Cancer. 2011 Dec 01;12(1):51-8
references.pmid: 22129804
references.citation: Oncogene. 2011 Mar 24;30(12):1379-89
references.pmid: 21119600
references.citation: Blood. 2011 Mar 17;117(11):3113-22
references.pmid: 21228324
references.citation: Blood. 1996 Oct 15;88(8):3065-73
references.pmid: 8874205
references.citation: AIDS Res Hum Retroviruses. 2013 Feb;29(2):359-64
references.pmid: 22894552
references.citation: Virol J. 2010 Apr 28;7:81
references.pmid: 20423527
references.citation: Bioinformatics. 2012 Mar 15;28(6):755-62
references.pmid: 22238265
references.citation: Semin Cancer Biol. 2014 Jun;26:89-98
references.pmid: 24316494
references.citation: Science. 2013 Mar 29;339(6127):1546-58
references.pmid: 23539594
references.citation: PLoS Pathog. 2008 Mar 21;4(3):e1000027
references.pmid: 18369476
references.citation: Eur J Immunol. 2009 Jul;39(7):1700-12
references.pmid: 19582737
references.citation: PLoS Comput Biol. 2014 Jun 19;10(6):e1003646
references.pmid: 24945836
references.citation: PLoS Pathog. 2013 Mar;9(3):e1003271
references.pmid: 23555266
references.citation: Cell. 2007 May 18;129(4):823-37
references.pmid: 17512414
references.citation: BMC Bioinformatics. 2011 Sep 14;12:367
references.pmid: 21914224
references.citation: Science. 2001 May 11;292(5519):1106-9
references.pmid: 11352065
references.citation: J Neurovirol. 1998 Dec;4(6):586-93
references.pmid: 10065900
references.citation: Blood. 2010 Aug 26;116(8):1211-9
references.pmid: 20448111
references.citation: PLoS Pathog. 2014 Mar 13;10(3):e1004006
references.pmid: 24626195
references.citation: Cancer Res. 2000 Feb 15;60(4):1043-8
references.pmid: 10706122
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3848-53
references.pmid: 10097126