title: CADM1 expression and stepwise downregulation of CD7 are closely associated with clonal expansion of HTLV-I-infected cells in adult T-cell leukemia/lymphoma.
abstract: OBJECTIVE
  Cell adhesion molecule 1 (CADM1), initially identified as a tumor suppressor gene, has recently been reported to be ectopically expressed in primary adult T-cell leukemia-lymphoma (ATL) cells. We incorporated CADM1 into flow-cytometric analysis to reveal oncogenic mechanisms in human T-cell lymphotrophic virus type I (HTLV-I) infection by purifying cells from the intermediate stages of ATL development.
  
  
  METHODS
  We isolated CADM1- and CD7-expressing peripheral blood mononuclear cells of asymptomatic carriers and ATLs using multicolor flow cytometry. Fluorescence-activated cell sorted (FACS) subpopulations were subjected to clonal expansion and gene expression analysis.
  
  
  RESULTS
  HTLV-I-infected cells were efficiently enriched in CADM1(+) subpopulations (D, CADM1(pos)CD7(dim) and N, CADM1(pos)CD7(neg)). Clonally expanding cells were detected exclusively in these subpopulations in asymptomatic carriers with high proviral load, suggesting that the appearance of D and N could be a surrogate marker of progression from asymptomatic carrier to early ATL. Further disease progression was accompanied by an increase in N with a reciprocal decrease in D, indicating clonal evolution from D to N. The gene expression profiles of D and N in asymptomatic carriers showed similarities to those of indolent ATLs, suggesting that these subpopulations represent premalignant cells. This is further supported by the molecular hallmarks of ATL, that is, drastic downregulation of miR-31 and upregulation of abnormal Helios transcripts.
  
  
  CONCLUSIONS
  The CADM1 versus CD7 plot accurately reflects disease progression in HTLV-I infection, and CADM1(+) cells with downregulated CD7 in asymptomatic carriers have common properties with those in indolent ATLs.
authors.affiliation: Authors' affiliations: Division of Molecular Therapy; Laboratory of Diagnostic Medicine, Division of Stem Cell Therapy; Department of Hematology/Oncology, Research Hospital; Clinical Laboratory, Research Hospital, Institute of Medical Science; and Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: Authors' affiliations: Division of Molecular Therapy; Laboratory of Diagnostic Medicine, Division of Stem Cell Therapy; Department of Hematology/Oncology, Research Hospital; Clinical Laboratory, Research Hospital, Institute of Medical Science; and Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Nakano
authors.affiliation: Authors' affiliations: Division of Molecular Therapy; Laboratory of Diagnostic Medicine, Division of Stem Cell Therapy; Department of Hematology/Oncology, Research Hospital; Clinical Laboratory, Research Hospital, Institute of Medical Science; and Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Watanabe
authors.affiliation: Authors' affiliations: Division of Molecular Therapy; Laboratory of Diagnostic Medicine, Division of Stem Cell Therapy; Department of Hematology/Oncology, Research Hospital; Clinical Laboratory, Research Hospital, Institute of Medical Science; and Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ishigaki
authors.affiliation: Authors' affiliations: Division of Molecular Therapy; Laboratory of Diagnostic Medicine, Division of Stem Cell Therapy; Department of Hematology/Oncology, Research Hospital; Clinical Laboratory, Research Hospital, Institute of Medical Science; and Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ohno
authors.affiliation: Authors' affiliations: Division of Molecular Therapy; Laboratory of Diagnostic Medicine, Division of Stem Cell Therapy; Department of Hematology/Oncology, Research Hospital; Clinical Laboratory, Research Hospital, Institute of Medical Science; and Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Yuji
authors.affiliation: Authors' affiliations: Division of Molecular Therapy; Laboratory of Diagnostic Medicine, Division of Stem Cell Therapy; Department of Hematology/Oncology, Research Hospital; Clinical Laboratory, Research Hospital, Institute of Medical Science; and Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Oyaizu
authors.affiliation: Authors' affiliations: Division of Molecular Therapy; Laboratory of Diagnostic Medicine, Division of Stem Cell Therapy; Department of Hematology/Oncology, Research Hospital; Clinical Laboratory, Research Hospital, Institute of Medical Science; and Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Asanuma
authors.affiliation: Authors' affiliations: Division of Molecular Therapy; Laboratory of Diagnostic Medicine, Division of Stem Cell Therapy; Department of Hematology/Oncology, Research Hospital; Clinical Laboratory, Research Hospital, Institute of Medical Science; and Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamagishi
authors.affiliation: Authors' affiliations: Division of Molecular Therapy; Laboratory of Diagnostic Medicine, Division of Stem Cell Therapy; Department of Hematology/Oncology, Research Hospital; Clinical Laboratory, Research Hospital, Institute of Medical Science; and Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Tadanori
authors.initials: T
authors.lastname: Yamochi
authors.affiliation: Authors' affiliations: Division of Molecular Therapy; Laboratory of Diagnostic Medicine, Division of Stem Cell Therapy; Department of Hematology/Oncology, Research Hospital; Clinical Laboratory, Research Hospital, Institute of Medical Science; and Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Watanabe
authors.affiliation: Authors' affiliations: Division of Molecular Therapy; Laboratory of Diagnostic Medicine, Division of Stem Cell Therapy; Department of Hematology/Oncology, Research Hospital; Clinical Laboratory, Research Hospital, Institute of Medical Science; and Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, JapanAuthors' affiliations: Division of Molecular Therapy; Laboratory of Diagnostic Medicine, Division of Stem Cell Therapy; Department of Hematology/Oncology, Research Hospital; Clinical Laboratory, Research Hospital, Institute of Medical Science; and Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Arinobu
authors.initials: A
authors.lastname: Tojo
authors.affiliation: Authors' affiliations: Division of Molecular Therapy; Laboratory of Diagnostic Medicine, Division of Stem Cell Therapy; Department of Hematology/Oncology, Research Hospital; Clinical Laboratory, Research Hospital, Institute of Medical Science; and Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Authors' affiliations: Division of Molecular Therapy; Laboratory of Diagnostic Medicine, Division of Stem Cell Therapy; Department of Hematology/Oncology, Research Hospital; Clinical Laboratory, Research Hospital, Institute of Medical Science; and Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan uchimaru@ims.u-tokyo.ac.jp.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Uchimaru
mesh_terms: D000328:Adult; D019011:Antigens, CD7 / Q000096:biosynthesis*; D014408:Biomarkers, Tumor / Q000032:analysis; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D015490:HTLV-I Infections / Q000378:metabolism*; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D019011:Antigens, CD7; D014408:Biomarkers, Tumor; C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins