Skip to main content
SpringerLink
Log in

Immunophenotype

  • Chapter
  • First Online:
Adult T-cell Leukemia/Lymphoma

Abstract

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of CD4(+) T cells. Pan-T markers such as CD2, CD3, and CD5 are expressed but most ATL cases lack CD7. Typical ATL cases are CD4(+)/CD8(−), but there are CD4(−)/CD8(+), CD4/8 double-positive, and double-negative cases. These CD8 antigens are induced on CD4 T cells. ATL cells express CCR4 and CD25, which are common in regulatory T cells. Furthermore, they express other regulatory T cell markers, such as GITR and CTLA4. These immunophenotypical similarities with regulatory T cells, along with the expression of FoxP3, a master regulator of regulatory T cell development, suggests that ATL cells may be derived from regulatory T cells. Because FoxP3 expression is induced by HBZ, the origin of ATL cells should be determined carefully in the future. Human T-cell leukemia virus type I (HTLV-I) infected cells alter their immunophenotype during the oncogenic process into ATL. CD3 is downregulated while cells infected with HTLV-1 proceed from an asymptomatic carrier state to ATL. CD7 and CD26 are also downregulated, whereas CADM1 expression is induced in this process. These immunophenotypic changes can be useful for detecting ATL cells and analyzing the oncogenic progression to ATL.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 119.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Ohshima, K., Jafe, E.S. and Kikuchi M. Adult T-cell leukemia/lymphoma. In: WHO classification of tumors of haematopoietic and lymphoid tissues. Lyon: IARC; 2008. p. 281–4.

    Google Scholar 

  2. Went P, et al. Marker expression in peripheral T-cell lymphoma: a proposed clinical-pathologic prognostic score. J Clin Oncol. 2006;24(16):2472–9.

    Article  CAS  PubMed  Google Scholar 

  3. Klemke CD, et al. Histopathological and immunophenotypical criteria for the diagnosis of Sézary syndrome in differentiation from other erythrodermic skin diseases: a European Organisation for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Task Force Study of 97 cases. Br J Dermatol. 2015;173(1):93–105.

    Article  CAS  PubMed  Google Scholar 

  4. Kamihira S, et al. Phenotypical diversity and prognosis of adult T-cell leukemia. Leuk Res. 1992;16(5):435–41.

    Article  CAS  PubMed  Google Scholar 

  5. Ramirez F, et al. Glucocorticoids induce the expression of CD8c chains on concanavalin A-activated rat CD4 + T cells: induction is inhibited by rat recombinant interleukin 4. J Exp Med. 1992;176(6):1551–9.

    Article  CAS  PubMed  Google Scholar 

  6. Yamada Y, et al. Established IL-2-dependent double-negative (CD4- CD8-) TCR alpha beta/CD3+ ATL cells: induction of CD4 expression. Br J Haematol. 1994;88(2):234–41.

    Article  CAS  PubMed  Google Scholar 

  7. Yaamada Y. Phenotypic and functional analysis of leukemic cells from 16 patients with adult T-cell leukemia/lymphoma. Blood. 1993;61(1):192–9.

    Google Scholar 

  8. Fazekas de St Groth B, Smith AL, Higgins CA. T cell activation: in vivo veritas. Immunol Cell Biol. 2004;82(3):260–8.

    Article  CAS  PubMed  Google Scholar 

  9. Shimabukuro-Vornhagen A, et al. Activated human B cells: stimulatory or tolerogenic antigen-presenting cells? Blood. 2009;114:746–7.

    Article  CAS  PubMed  Google Scholar 

  10. Triplett TA, et al. Defining a functionally distinct subset of human memory CD4+ T cells that are CD25POS and FOXP3NEG. Eur J Immunol. 2012;42(7):1893–905.

    Article  CAS  PubMed  Google Scholar 

  11. Sakaguchi S. Regulatory T cells: history and perspective. Methods Mol Biol. 2011;707:3–17.

    Article  CAS  PubMed  Google Scholar 

  12. Yodoi J, Maeda M. Discovery of ATL: an odyssey in restrospect. Int J Hematol. 2011;94(5):423–8.

    Article  CAS  PubMed  Google Scholar 

  13. Turturro F. Denileukin diftitox: a biotherapeutic paradigm shift in the treatment of lymphoid-derived disorders. Expert Rev Anticancer Ther. 2007;7(1):11–7.

    Article  CAS  PubMed  Google Scholar 

  14. Tobinai K. Clinical trials for human T-cell lymphotropic virus type I-associated peripheral T-cell lymphoma in Japan. Semin Hematol. 2010;47(Suppl 1):S5–7.

    Article  CAS  PubMed  Google Scholar 

  15. Berkowitz JL, et al. Safety, efficacy, and pharmacokinetics/pharmacodynamics of daclizumab (anti-CD25) in patients with adult T-cell leukemia/lymphoma. Clin Immunol. 2014;155(2):176–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kreitman RJ, et al. Phase I trial of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) in patients with hematologic malignancies. J Clin Oncol. 2000;18(8):1622–36.

    Article  CAS  PubMed  Google Scholar 

  17. Kreitman RJ, et al. Complete remissions of adult T-cell leukemia with anti-CD25 recombinant immunotoxin LMB-2 and chemotherapy to block immunogenicity. Clin Cancer Res. 2015;22:310–8.

    Article  PubMed  Google Scholar 

  18. Hanafusa T, et al. Flow cytometric immunophenotyping of adult T-cell leukemia/lymphoma using CD3 gating. Am J Clin Pathol. 2005;124(2):199–204.

    Article  PubMed  Google Scholar 

  19. Akl H, et al. HTLV-I infection of WE17/10 CD4+ cell line leads to progressive alteration of Ca2+ influx that eventually results in loss of CD7 expression and activation of an antiapoptotic pathway involving AKT and BAD which paves the way for malignant transformation. Leukemia. 2007;21(4):788–96.

    CAS  PubMed  Google Scholar 

  20. Akl H, et al. Progressive loss of CD3 expression after HTLV-I infection results from chromatin remodeling affecting all the CD3 genes and persists despite early viral genes silencing. Virol J. 2007;4:85.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Tian Y, et al. Leukemic T cells are specifically enriched in a unique CD3(dim) CD7(low) subpopulation of CD4(+) T cells in acute-type adult T-cell leukemia. Cancer Sci. 2011;102(3):569–77.

    Article  CAS  PubMed  Google Scholar 

  22. Zlotnik A, Yoshie O, Nomiyama H. The chemokine and chemokine receptor superfamilies and their molecular evolution. Genome Biol. 2006;7(12):243.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Griffith JW, Sokol CL, Luster AD. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu Rev Immunol. 2014;32:659–702.

    Article  CAS  PubMed  Google Scholar 

  24. Imai T, et al. Selective recruitment of CCR4-bearing Th2 cells toward antigen-presenting cells by the CC chemokines thymus and activation-regulated chemokine and macrophage-derived chemokine. Int J Immunol. 1999;11(1):81–8.

    Article  CAS  Google Scholar 

  25. Curiel TJ, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10(9):942–9.

    Article  CAS  PubMed  Google Scholar 

  26. Takashi Ishida AU, Iida S, et al. Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome. Clin Cancer Res. 2003;9(10):3625–34.

    PubMed  Google Scholar 

  27. Ohshima K, et al. Classification of distinct subtypes of peripheral T-cell lymphoma unspecified, identified by chemokine and chemokine receptor expression: analysis of prognosis. Int J Oncol. 2004;25(3):605–13.

    CAS  PubMed  Google Scholar 

  28. Ishii T, et al. Defucosylated humanized anti-CCR4 monoclonal antibody KW-0761 as a novel immunotherapeutic agent for adult T-cell leukemia/lymphoma. Clin Cancer Res. 2010;16(5):1520–31.

    Article  CAS  PubMed  Google Scholar 

  29. Ishida T, et al. Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study. J Clin Oncol. 2012;30(8):837–42.

    Article  CAS  PubMed  Google Scholar 

  30. Ishida T, et al. Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study. Br J Haematol. 2015;169(5):672–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ruckes T, et al. Autocrine antiapoptotic stimulation of cultured adultT-cell leukemia cells by overexpression of the chemokine I-309. Blood. 2001;98(4):1150–9.

    Google Scholar 

  32. Hasegawa H, et al. Increased chemokine receptor CCR7/EBI1 expression enhances the infiltration of lymphoid organs by adult T-cell leukemia cells. Blood. 2000;95(1):30–8.

    CAS  PubMed  Google Scholar 

  33. Harasawa H, et al. Survey of chemokine receptor expression reveals frequent co-expression of skin-homing CCR4 and CCR10 in adult T-cell leukemia/lymphoma. Leuk Lymphoma. 2006;47(10):2163–73.

    Article  CAS  PubMed  Google Scholar 

  34. Horikawa T, et al. IFN-gamma-inducible expression of thymus and activation-regulated chemokine/CCL17 and macrophage-derived chemokine/CCL22 in epidermal keratinocytes and their roles in atopic dermatitis. Int Immunol. 2002;14(7):767–73.

    Article  CAS  PubMed  Google Scholar 

  35. Wang W, et al. Identification of a novel chemokine (CCL28), which binds CCR10 (GPR2). J Biol Chem. 2000;275(29):22313–23.

    Article  CAS  PubMed  Google Scholar 

  36. Pan J, et al. Cutting edge: a novel chemokine ligand for CCR10 and CCR3 expressed by epithelial cells in mucosal tissues. J Immunol. 2000;165(6):2943–9.

    Article  CAS  PubMed  Google Scholar 

  37. Sakaguchi S, et al. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10(7):490–500.

    Article  CAS  PubMed  Google Scholar 

  38. Ronchetti S, et al. Glucocorticoid-induced tumour necrosis factor receptor-related protein: a key marker of functional regulatory T cells. J Immunol Res. 2015;2015:171520.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Takahashi T, et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte–associated antigen 4. J Exp Med. 2000;192(2):303–9.

    Google Scholar 

  40. Kohno T, et al. Possible origin of adult T-cell leukemia/lymphoma cells from human T lymphotropic virus type-1-infected regulatory T cells. Cancer Sci. 2005;96(8):527–33.

    Article  CAS  PubMed  Google Scholar 

  41. Matsubara Y, et al. Phenotypic and functional relationship between adult T-cell leukemia cells and regulatory T cells. Leukemia. 2005;19(3):482–3.

    Article  CAS  PubMed  Google Scholar 

  42. Ohkura N, Kitagawa Y, Sakaguchi S. Development and maintenance of regulatory T cells. Immunity. 2013;38(3):414–23.

    Article  CAS  PubMed  Google Scholar 

  43. Karube K, et al. Expression of FoxP3, a key molecule in CD4CD25 regulatory T cells, in adult T-cell leukaemia/lymphoma cells. Br J Haematol. 2004;126(1):81–4.

    Article  CAS  PubMed  Google Scholar 

  44. Satou Y, et al. HTLV-1 modulates the frequency and phenotype of FoxP3 + CD4+ T cells in virus-infected individuals. Retrovirology. 2012;9:46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Gaudray G, et al. The complementary strand of the human T-cell leukemia virus type 1 RNA genome encodes a bZIP transcription factor that down-regulates viral transcription. J Virol. 2002;76(24):12813–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Satou Y, et al. HTLV-1 bZIP factor induces T-cell lymphoma and systemic inflammation in vivo. PLoS Pathog. 2011;7(2):e1001274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Schneider YJ, et al. The role of receptor-mediated endocytosis in iron metabolism. Prog Clin Biol Res. 1982;91:495–521.

    CAS  PubMed  Google Scholar 

  48. Trowbridge IS, Shackelford DA. Structure and function of transferrin receptors and their relationship to cell growth. Biochem Soc Symp. 1986;51:117–29.

    CAS  PubMed  Google Scholar 

  49. Gatter KC, et al. Transferrin receptors in human tissues: their distribution and possible clinical relevance. J Clin Pathol. 1983;36(5):539–45.

    Google Scholar 

  50. Vidal C, et al. Human T lymphotropic virus I infection deregulates surface expression of the transferrin receptor. J Immunol. 1988;141(3):984–8.

    Google Scholar 

  51. Moura IC, et al. Aneutralizing monoclonal antibody (mAbA24) directed against the transferrin receptor induces apoptosis of tumor T lymphocytes from ATL patients. Blood. 2004;103(5):1838–45.

    Google Scholar 

  52. Yamazaki J, et al. Identification of cancer stem cells in a Tax-transgenic (Tax-Tg) mouse model of adult T-cell leukemia/lymphoma. Blood. 2009;114(13):2709–20.

    Article  CAS  PubMed  Google Scholar 

  53. Yonehara S, et al. A cell-killing monoclonal antibody (ANTI-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor. J Exp Med. 1989;169(5):1747–56.

    Google Scholar 

  54. Kamihira S, et al. Quantitative characterization and potential function of membrane Fas/APO-1 (CD95) receptors on leukaemic cells from chronic B and T lymphoid leukaemias. Br J Haematol. 1997;99(4):858–65.

    Google Scholar 

  55. Krueger A, et al. HTLV-1Tax protects against CD95-mediated apoptosis by induction of the cellular FLICE-inhibitory protein (c-FLIP). Blood. 2006;107(10):3933–9.

    Google Scholar 

  56. Okamoto K, et al. Human T-cell leukemia virus type-I oncoprotein Tax inhibits Fas-mediated apoptosis by inducing cellular FLIP through activation of NF-kappaB. Genes Cells. 2006;11(2):177–91.

    Article  CAS  PubMed  Google Scholar 

  57. Wang W, et al. Human T-cell leukemia virus type 1 Tax-deregulated autophagy pathway and c-FLIP expression contribute to resistance against death receptor-mediated apoptosis. J Virol. 2014;88(5):2786–98.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Maeda T, et al. Fas gene mutation in the progression of adult T cell leukemia. J Exp Med. 1999;189(7):1063–71.

    Google Scholar 

  59. Sugahara K, et al. Soluble and membrane isoforms of Fas/CD95 in fresh adult T-cell leukemia (ATL) cells and ATL-cell lines. Int J Cancer. 1997;72(1):128–32.

    Google Scholar 

  60. Safa AR. c-FLIP, a master anti-apoptotic regulator. Exp Oncol. 2012;34(3):176–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Ashkenazi A, Dixit VM. Apoptosis control by death and decoy receptors. Curr Opin Cell Biol. 1999;11(2):255–60.

    Article  CAS  PubMed  Google Scholar 

  62. Hasegawa H, et al. Sensitivity of adult T-cell leukaemia lymphoma cells to tumour necrosis factor-related apoptosis-inducing ligand. Br J Haematol. 2005;128(2):253–65.

    Article  CAS  PubMed  Google Scholar 

  63. Ding J, et al. Wogonin and related natural flavones overcome tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein resistance of tumors by down-regulation of c-FLIP protein and up-regulation of TRAIL receptor 2 expression. J Biol Chem. 2012;287(1):641–9.

    Article  CAS  PubMed  Google Scholar 

  64. Murakami Y. Involvement of a cell adhesion molecule, TSLC1/IGSF4, in human oncogenesis. Cancer Sci. 2005;96(9):543–52.

    Article  CAS  PubMed  Google Scholar 

  65. Galibert L, et al. Nectin-like protein 2 defines a subset of T-cell zone dendritic cells and is a ligand for class-I-restricted T-cell-associated molecule. J Biol Chem. 2005;280(23):21955–64.

    Article  CAS  PubMed  Google Scholar 

  66. Watabe K, et al. IGSF4: a new intercellular adhesion molecule that is called by three names, TSLC1, SgIGSF and SynCAM, by virtue of its diverse function. Histol Histopathol. 2003;18(4):1321–9.

    CAS  PubMed  Google Scholar 

  67. Sasaki H, et al. Overexpression of a cell adhesion molecule, TSLC1, as a possible molecular marker for acute-type adult T-cell leukemia. Blood. 2005;105(3):1204–13.

    Article  CAS  PubMed  Google Scholar 

  68. Nakahata S, et al. Clinical significance of CADM1/TSLC1/IgSF4 expression in adult T-cell leukemia/lymphoma. Leukemia. 2012;26(6):1238–46.

    Article  CAS  PubMed  Google Scholar 

  69. Nakahata S, et al. CADM1/TSLC1 is a novel cell surface marker for adult T-cell leukemia/lymphoma. J Clin Exp Hematop. 2012;52(1):17–22.

    Google Scholar 

  70. Kobayashi S, et al. CADM1 expression and stepwise downregulation of CD7 are closely associated with clonal expansion of HTLV-I-infected cells in adult T-cell leukemia/lymphoma. Clin Cancer Res. 2014;20(11):2851–61.

    Article  CAS  PubMed  Google Scholar 

  71. Yamagishi M, et al. Polycomb-mediated loss of miR-31 activates NIK-dependent NF-kappaB pathway in adult T cell leukemia and other cancers. Cancer Cell. 2012;21(1):121–35.

    Article  CAS  PubMed  Google Scholar 

  72. Asanuma S, et al. Adult T-cell leukemia cells are characterized by abnormalities of Helios expression that promote T cell growth. Cancer Sci. 2013;104(8):1097–106.

    Article  CAS  PubMed  Google Scholar 

  73. Takahashi R, et al. Epigenetic deregulation of Ellis Van Creveld confers robust Hedgehog signaling in adult T-cell leukemia. Cancer Sci. 2014;105(9):1160–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kobayashi S, et al. Advanced human T-cell leukemia virus type 1 carriers and early-stage indolent adult T-cell leukemia-lymphoma are indistinguishable based on CADM1 positivity in flow cytometry. Cancer Sci. 2015;106(5):598–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Iwata S, et al. CD26/dipeptidyl peptidase IV in context: the different roles of a multifunctional ectoenzyme in malignant transformation. J Exp Med. 1999;190(3):301–5.

    Google Scholar 

  76. Ohnuma K, Dang NH, Morimoto C. Revisiting an old acquaintance: CD26 and its molecular mechanisms in T cell function. Trends Immunol. 2008;29(6):295–301.

    Article  CAS  PubMed  Google Scholar 

  77. Jones D, et al. Absence of CD26 expression is a useful marker for diagnosis of T-cell lymphoma in peripheral' blood. Am J Clin Pathol. 2001;115(6):885–92.

    Google Scholar 

  78. Bauvois B, et al. Constitutive expression of CD26/dipeptidylpeptidase IV on peripheral blood B lymphocytes of patients with B chronic lymphocytic leukaemia. Br J Cancer. 1999;79(7/8):1042–8.

    Google Scholar 

  79. Morrison ME, et al. A marker for neoplastic progression of human melanocytes is a cell surface ectopeptidase. J Exp Med. 1993;177(4):1135–43.

    Google Scholar 

  80. Amatya VJ, et al. Overexpression of CD26/DPPIV in mesothelioma tissue and mesothelioma cell lines. Oncol Rep. 2011;26(6):1369–75.

    PubMed  Google Scholar 

  81. Tsuji T, et al. Clinical and oncologic implications in epigenetic down-regulation of CD26/dipeptidyl peptidase IV in adult T-cell leukemia cells. Int J Hematol. 2004;80(3):254–60.

    Article  CAS  PubMed  Google Scholar 

  82. Kamihira S, et al. Heterogeneity in clonal nature in the smoldering subtype of adult T-cell leukemia: continuity from carrier status to smoldering ATL. Int J Hematol. 2012;95(4):399–408.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology/Oncology, Research Hospital, Institute of Medical Science, the University of Tokyo, Tokyo, Japan

    Kaoru Uchimaru

Authors
  1. Kaoru Uchimaru
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kaoru Uchimaru .

Editor information

Editors and Affiliations

  1. Department of Medical Genome Sciences Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan

    Toshiki Watanabe

  2. Department of Clinical Laboratory Sciences School of Health Sciences, University of the Ryukyus, Okinawa, Japan

    Takuya Fukushima

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Japan KK

About this chapter

Cite this chapter

Uchimaru, K. (2017). Immunophenotype. In: Watanabe, T., Fukushima, T. (eds) Adult T-cell Leukemia/Lymphoma. Springer, Tokyo. https://doi.org/10.1007/978-4-431-56523-9_5

Download citation

  • DOI: https://doi.org/10.1007/978-4-431-56523-9_5

  • Published:

  • Publisher Name: Springer, Tokyo

  • Print ISBN: 978-4-431-56521-5

  • Online ISBN: 978-4-431-56523-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation