Advertisement

Current Hematologic Malignancy Reports

, Volume 13, Issue 4, pp 318–328 | Cite as

Molecular Insights Into Pathogenesis of Peripheral T Cell Lymphoma: a Review

  • Waseem Lone
  • Aisha Alkhiniji
  • Jayadev Manikkam Umakanthan
  • Javeed Iqbal
T-Cell and Other Lymphoproliferative Malignancies (J Zain, Section Editor)
Part of the following topical collections:
  1. Topical Collection on T-Cell and Other Lymphoproliferative Malignancies

Abstract

Purpose of Review

Peripheral T cell lymphoma (PTCL) is a heterogeneous group of lymphoproliferative neoplasms, with at least 29 distinct entities described in current WHO classification. Using present diagnostic approaches, more than a third of PTCL cases cannot be classified, hence designated as PTCL-not otherwise specified (PTCL-NOS). Herein, we summarize the current genomic findings and their role in the molecular pathogenesis in different PTCL entities.

Recent Findings

Gene expression profiling (GEP) studies have identified distinct molecular signatures for accurate diagnosis and elucidated oncogenic pathways enriched in major PTCL entities. Furthermore, genomic characterization has identified recurrent somatic mutations and potential therapeutic targets. Further efforts are underway to develop genetically faithful murine models.

Summary

GEP studies have identified molecular subgroups of PTCL, characterized by distinct genetic and epigenetic alterations. Understanding the molecular mechanisms of T cell lymphomagenesis using in vivo model will help to reveal novel therapeutic targets.

Keywords

PTCL Peripheral T cell lymphoma-not otherwise specified Angioimmunoblastic T cell lymphoma Anaplastic large cell lymphoma Gene expression profiling Molecular signature 

Notes

Compliance with Ethical Standards

Conflict of Interest

Waseem Lone, Aisha Alkhiniji, Jayadev Manikkam Umakanthan, and Javeed Iqbal declare they have no conflict of interests.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major Importance

  1. 1.
    Bellei M, Chiattone CS, Luminari S, Pesce EA, Cabrera ME, de Souza CA, et al. T-cell lymphomas in South America and Europe. Rev Bras Hematol Hemoter. 2012;34(1):42–7.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Arora N, Manipadam MT, Nair S. Frequency and distribution of lymphoma types in a tertiary care hospital in South India: analysis of 5115 cases using the World Health Organization 2008 classification and comparison with world literature. Leuk Lymphoma. 2013;54(5):1004–11.PubMedGoogle Scholar
  3. 3.
    Rudiger T, Weisenburger DD, Anderson JR, et al. Peripheral T-cell lymphoma (excluding anaplastic large-cell lymphoma): results from the Non-Hodgkin’s Lymphoma Classification Project. Ann Oncol. 2002;13(1):140–9.PubMedGoogle Scholar
  4. 4.
    Perry AM, Diebold J, Nathwani BN, MacLennan KA, Müller-Hermelink HK, Bast M, et al. Non-Hodgkin lymphoma in the Far East: review of 730 cases from the International Non-Hodgkin Lymphoma Classification Project. Ann Hematol. 2016;95(2):245–51.PubMedGoogle Scholar
  5. 5.
    Swerdlow SH, Campo E, Harris NL, et al. WHO classification: pathology and genetics of tumors of haematopoietic and lymphoid tissues. WHO;4. Lyon,France: IARC Press; 2008.Google Scholar
  6. 6.
    Hock J, Meister G. The Argonaute protein family. Genome Biol. 2008;9(2):210.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Briski R, Feldman AL, Bailey NG, Lim MS, Ristow K, Habermann TM, et al. The role of front-line anthracycline-containing chemotherapy regimens in peripheral T-cell lymphomas. Blood Cancer J. 2014;4:e214.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Parrilla Castellar ER, Jaffe ES, Said JW, Swerdlow SH, Ketterling RP, Knudson RA, et al. ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. Blood. 2014;124(9):1473–80.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Escalon MP, Liu NS, Yang Y, et al. Prognostic factors and treatment of patients with T-cell non-Hodgkin lymphoma: the M. D. Anderson Cancer Center experience. Cancer. 2005;103(10):2091–8.PubMedGoogle Scholar
  10. 10.
    Croziera JA, Shera T, Yangb D et al. Persistent disparities among patients with T-cell non-Hodgkin lymphomas and B-cell diffuse large cell lymphomas over 40 years: a SEER database review. Clin Lymphoma Myeloma Leuk. 2015;15(10):578–85.Google Scholar
  11. 11.
    Xu B, Liu P. No survival improvement for patients with angioimmunoblastic T-cell lymphoma over the past two decades: a population-based study of 1207 cases. PLoS One. 2014;9(3):e92585.PubMedPubMedCentralGoogle Scholar
  12. 12.
    • Iqbal J, Wright G, Wang C, Rosenwald A, Gascoyne RD, Weisenburger DD, et al. Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma. Blood. 2014;123(19):2915–23. This study identified novel molecular subgroups with prognostic information within PTCL-NOS using GEP. PubMedPubMedCentralGoogle Scholar
  13. 13.
    Iqbal J, Weisenburger DD, Greiner TC, Vose JM, McKeithan T, Kucuk C, et al. Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma. Blood. 2010;115(5):1026–36.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Iqbal J, Weisenburger DD, Chowdhury A, et al. Natural killer cell lymphoma shares strikingly similar molecular features with a group of non-hepatosplenic gammadelta T-cell lymphoma and is highly sensitive to a novel aurora kinase A inhibitor in vitro. Leukemia. 2011;25(2):348–58.PubMedGoogle Scholar
  15. 15.
    Pizzi M, Margolskee E, Inghirami G. Pathogenesis of peripheral T cell lymphoma. Annu Rev Pathol. 2018;13:293–320.PubMedGoogle Scholar
  16. 16.
    Martin CH, Aifantis I, Scimone ML, von Andrian UH, Reizis B, von Boehmer H, et al. Efficient thymic immigration of B220+ lymphoid-restricted bone marrow cells with T precursor potential. Nat Immunol. 2003;4(9):866–73.PubMedGoogle Scholar
  17. 17.
    Germain RN. T-cell development and the CD4-CD8 lineage decision. Nat Rev Immunol. 2002;2(5):309–22.PubMedGoogle Scholar
  18. 18.
    Poltorak M, Meinert I, Stone JC, Schraven B, Simeoni L. Sos1 regulates sustained TCR-mediated Erk activation. Eur J Immunol. 2014;44(5):1535–40.PubMedGoogle Scholar
  19. 19.
    Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13(4):227–42.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Tsuchiya T, Ohshima K, Karube K, Yamaguchi T, Suefuji H, Hamasaki M, et al. Th1, Th2, and activated T-cell marker and clinical prognosis in peripheral T-cell lymphoma, unspecified: comparison with AILD, ALCL, lymphoblastic lymphoma, and ATLL. Blood. 2004;103(1):236–41.PubMedGoogle Scholar
  21. 21.
    Hegazy AN, Peine M, Helmstetter C, Panse I, Fröhlich A, Bergthaler A, et al. Interferons direct Th2 cell reprogramming to generate a stable GATA-3(+)T-bet(+) cell subset with combined Th2 and Th1 cell functions. Immunity. 2010;32(1):116–28.PubMedGoogle Scholar
  22. 22.
    Bouska A, McKeithan TW, Deffenbacher KE, et al. Genome-wide copy-number analyses reveal genomic abnormalities involved in transformation of follicular lymphoma. Blood. 2014;123(11):1681–90.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Bouska A, Zhang W, Gong Q, Iqbal J, Scuto A, Vose J, et al. Combined copy number and mutation analysis identifies oncogenic pathways associated with transformation of follicular lymphoma. Leukemia. 2017;31(1):83–91.PubMedGoogle Scholar
  24. 24.
    Cairns RA, Iqbal J, Lemonnier F, Kucuk C, de Leval L, Jais JP, et al. IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. Blood. 2012;119(8):1901–3.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Guo S, Chan JK, Iqbal J, et al. EZH2 mutations in follicular lymphoma from different ethnic groups and associated gene expression alterations. Clin Cancer Res. 2014;20(12):3078–86.PubMedGoogle Scholar
  26. 26.
    Kucuk C, Hu X, Jiang B, Klinkebiel D, Geng H, Gong Q, et al. Global promoter methylation analysis reveals novel candidate tumor suppressor genes in natural killer cell lymphoma. Clin Cancer Res. 2015;21(7):1699–711.PubMedPubMedCentralGoogle Scholar
  27. 27.
    McKinney M, Moffitt AB, Gaulard P, Travert M, de Leval L, Nicolae A, et al. The genetic basis of hepatosplenic T-cell lymphoma. Cancer Discov. 2017;7(4):369–79.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Weisenburger DD, Savage KJ, Harris NL, Gascoyne RD, Jaffe ES, MacLennan KA, et al. Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project. Blood. 2011;117(12):3402–8.PubMedGoogle Scholar
  29. 29.
    • de Leval L, Rickman DS, Thielen C, Reynies A, Huang YL, Delsol G, et al. The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells. Blood. 2007;109(11):4952–63. First description of T FH cells as the cell of origin in AITL using GEP. PubMedGoogle Scholar
  30. 30.
    Martinez-Delgado B. Peripheral T-cell lymphoma gene expression profiles. Hematol Oncol. 2006;24(3):113–9.PubMedGoogle Scholar
  31. 31.
    Piccaluga PP, Agostinelli C, Califano A, Carbone A, Fantoni L, Ferrari S, et al. Gene expression analysis of angioimmunoblastic lymphoma indicates derivation from T follicular helper cells and vascular endothelial growth factor deregulation. Cancer Res. 2007;67(22):10703–10.PubMedGoogle Scholar
  32. 32.
    Cuadros M, Dave SS, Jaffe ES, Honrado E, Milne R, Alves J, et al. Identification of a proliferation signature related to survival in nodal peripheral T-cell lymphomas. J Clin Oncol Off J Am Soc Clin Oncol. 2007;25(22):3321–9.Google Scholar
  33. 33.
    Martinez-Delgado B, Cuadros M, Honrado E, et al. Differential expression of NF-kappaB pathway genes among peripheral T-cell lymphomas. Leukemia. 2005;19(12):2254–63.PubMedGoogle Scholar
  34. 34.
    Ballester B, Ramuz O, Gisselbrecht C, Doucet G, Loï L, Loriod B, et al. Gene expression profiling identifies molecular subgroups among nodal peripheral T-cell lymphomas. Oncogene. 2006;25(10):1560–70.PubMedGoogle Scholar
  35. 35.
    Wang C, Collins M, Kuchroo VK. Effector T cell differentiation: are master regulators of effector T cells still the masters? Curr Opin Immunol. 2015;37:6–10.PubMedGoogle Scholar
  36. 36.
    O’Shea JJ, Paul WE. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science. 2010;327(5969):1098–102.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Schatz JH, Horwitz SM, Teruya-Feldstein J, Lunning MA, Viale A, Huberman K, et al. Targeted mutational profiling of peripheral T-cell lymphoma not otherwise specified highlights new mechanisms in a heterogeneous pathogenesis. Leukemia. 2015;29(1):237–41.PubMedGoogle Scholar
  38. 38.
    Lemonnier F, Couronne L, Parrens M, Jais JP, Travert M, Lamant L, et al. Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters. Blood. 2012;120(7):1466–9.PubMedGoogle Scholar
  39. 39.
    Boddicker RL, Razidlo GL, Dasari S, Zeng Y, Hu G, Knudson RA, et al. Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma. Blood. 2016;128(9):1234–45.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Vasmatzis G, Johnson SH, Knudson RA, Ketterling RP, Braggio E, Fonseca R, et al. Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas. Blood. 2012;120(11):2280–9.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Vose J, Armitage J, Weisenburger D. International TCLP. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(25):4124–30.Google Scholar
  42. 42.
    •• Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375–90. Updated WHO ( 2016 ) classification of lymphoid neoplasms. PubMedPubMedCentralGoogle Scholar
  43. 43.
    Dunleavy K, Wilson WH, Jaffe ES. Angioimmunoblastic T cell lymphoma: pathobiological insights and clinical implications. Curr Opin Hematol. 2007;14(4):348–53.PubMedGoogle Scholar
  44. 44.
    Federico M, Rudiger T, Bellei M, Nathwani BN, Luminari S, Coiffier B, et al. Clinicopathologic characteristics of angioimmunoblastic T-cell lymphoma: analysis of the international peripheral T-cell lymphoma project. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(2):240–6.Google Scholar
  45. 45.
    Iqbal J, Shen Y, Liu Y, Fu K, Jaffe ES, Liu C, et al. Genome-wide miRNA profiling of mantle cell lymphoma reveals a distinct subgroup with poor prognosis. Blood. 2012;119(21):4939–48.PubMedPubMedCentralGoogle Scholar
  46. 46.
    de Leval L, Gisselbrecht C, Gaulard P. Advances in the understanding and management of angioimmunoblastic T-cell lymphoma. Br J Haematol. 2010;148(5):673–89.PubMedGoogle Scholar
  47. 47.
    Gaulard P, de Leval L. The microenvironment in T-cell lymphomas: emerging themes. Semin Cancer Biol. 2014;24:49–60.PubMedGoogle Scholar
  48. 48.
    de Leval L, Gaulard P. Cellular origin of T-cell lymphomas. Blood. 2014;123(19):2909–10.PubMedGoogle Scholar
  49. 49.
    Grogg KL, Attygalle AD, Macon WR, Remstein ED, Kurtin PJ, Dogan A. Angioimmunoblastic T-cell lymphoma: a neoplasm of germinal-center T-helper cells? Blood. 2005;106(4):1501–2.PubMedPubMedCentralGoogle Scholar
  50. 50.
    •• Palomero T, Couronne L, Khiabanian H, et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet. 2014;46(2):166–70. This study performed the whole exome sequencing, RNAseq analysis and targeted deep sequencing to identify new genetic alterations in PTCL transformation.PubMedPubMedCentralGoogle Scholar
  51. 51.
    •• Sakata-Yanagimoto M, Enami T, Yoshida K, Shiraishi Y, Ishii R, Miyake Y, et al. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat Genet. 2014;46(2):171–5. This study demonstrated that impaired RHOA function in cooperation with preceding loss of TET2 function contributes to AITL-specific pathogenesis.PubMedGoogle Scholar
  52. 52.
    •• Yoo HY, Sung MK, Lee SH, Kim S, Lee H, Park S, et al. A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma. Nat Genet. 2014;46(4):371–5. These three studies identified RHOA G17V as the recurrent mutation in AITL. PubMedGoogle Scholar
  53. 53.
    Odejide O, Weigert O, Lane AA, Toscano D, Lunning MA, Kopp N, et al. A targeted mutational landscape of angioimmunoblastic T-cell lymphoma. Blood. 2014;123(9):1293–6.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Jiang L, Gu ZH, Yan ZX, Zhao X, Xie YY, Zhang ZG, et al. Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma. Nat Genet. 2015;47(9):1061–6.PubMedGoogle Scholar
  55. 55.
    Kataoka K, Nagata Y, Kitanaka A, Shiraishi Y, Shimamura T, Yasunaga JI, et al. Integrated molecular analysis of adult T cell leukemia/lymphoma. Nat Genet. 2015;47(11):1304–15.PubMedGoogle Scholar
  56. 56.
    Nagata Y, Kontani K, Enami T, Kataoka K, Ishii R, Totoki Y, et al. Variegated RHOA mutations in adult T-cell leukemia/lymphoma. Blood. 2016;127(5):596–604.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Vallois D, Dobay MP, Morin RD, et al. Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas. Blood. 2016;128(11):1490–502.PubMedGoogle Scholar
  58. 58.
    • Wang C, McKeithan TW, Gong Q, et al. IDH2R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma. Blood. 2015;126(15):1741–52. This study showed specificty of IDH2 R172 mutations with AITL entity. PubMedPubMedCentralGoogle Scholar
  59. 59.
    Moffitt AB, Dave SS. Clinical applications of the genomic landscape of aggressive non-Hodgkin lymphoma. J Clin Oncol. 2017;35(9):955–62.PubMedGoogle Scholar
  60. 60.
    Borroto A, Gil D, Delgado P, Vicente-Manzanares M, Alcover A, Sánchez-Madrid F, et al. Rho regulates T cell receptor ITAM-induced lymphocyte spreading in an integrin-independent manner. Eur J Immunol. 2000;30(12):3403–10.PubMedGoogle Scholar
  61. 61.
    Rougerie P, Delon J. Rho GTPases: masters of T lymphocyte migration and activation. Immunol Lett. 2012;142(1–2):1–13.PubMedGoogle Scholar
  62. 62.
    Manso R, Sanchez-Beato M, Monsalvo S, Gomez S, Cereceda L, Llamas P, et al. The RHOA G17V gene mutation occurs frequently in peripheral T-cell lymphoma and is associated with a characteristic molecular signature. Blood. 2014;123(18):2893–4.PubMedGoogle Scholar
  63. 63.
    Mereu E, Pellegrino E, Scarfo I, Inghirami G, Piva R. The heterogeneous landscape of ALK negative ALCL. Oncotarget. 2017;8(11):18525–36.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Bonzheim I, Geissinger E, Roth S, Zettl A, Marx A, Rosenwald A, et al. Anaplastic large cell lymphomas lack the expression of T-cell receptor molecules or molecules of proximal T-cell receptor signaling. Blood. 2004;104(10):3358–60.PubMedGoogle Scholar
  65. 65.
    Morris SW, Kirstein MN, Valentine MB, Dittmer K, Shapiro DN, Look AT, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science. 1995;267(5196):316–7.PubMedGoogle Scholar
  66. 66.
    Mason DY, Bastard C, Rimokh R, Dastugue N, Huret JL, Kristoffersson U, et al. CD30-positive large cell lymphomas (‘Ki-1 lymphoma’) are associated with a chromosomal translocation involving 5q35. Br J Haematol. 1990;74(2):161–8.PubMedGoogle Scholar
  67. 67.
    Morris SW, Kirstein MN, Valentine MB, Dittmer K, Shapiro D, Saltman D, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science. 1994;263(5151):1281–4.PubMedGoogle Scholar
  68. 68.
    Rimokh R, Magaud JP, Berger F, Samarut J, Coiffier B, Germain D, et al. A translocation involving a specific breakpoint (q35) on chromosome 5 is characteristic of anaplastic large cell lymphoma (‘Ki-1 lymphoma’). Br J Haematol. 1989;71(1):31–6.PubMedGoogle Scholar
  69. 69.
    Savage KJ, Harris NL, Vose JM, Ullrich F, Jaffe ES, Connors JM, et al. ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood. 2008;111(12):5496–504.PubMedGoogle Scholar
  70. 70.
    Crescenzo R, Abate F, Lasorsa E, Tabbo’ F, Gaudiano M, Chiesa N, et al. Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell. 2015;27(4):516–32.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Clemens MW, Medeiros LJ, Butler CE, Hunt KK, Fanale MA, Horwitz S, et al. Complete surgical excision is essential for the management of patients with breast implant-associated anaplastic large-cell lymphoma. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34(2):160–8.Google Scholar
  72. 72.
    Kawada H, Yoshimitsu M, Nakamura D, Arai A, Hayashida M, Kamada Y, et al. A retrospective analysis of treatment outcomes in adult T cell leukemia/lymphoma patients with aggressive disease treated with or without allogeneic stem cell transplantation: a single-center experience. Biol Blood Marrow Transplant. 2015;21(4):696–700.PubMedGoogle Scholar
  73. 73.
    Taylor GP, Matsuoka M. Natural history of adult T-cell leukemia/lymphoma and approaches to therapy. Oncogene. 2005;24(39):6047–57.PubMedGoogle Scholar
  74. 74.
    Sasaki H, Nishikata I, Shiraga T, Akamatsu E, Fukami T, Hidaka T, 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.PubMedGoogle Scholar
  75. 75.
    Pise-Masison CA, Radonovich M, Dohoney K, Morris JC, O’Mahony D, Lee MJ, et al. Gene expression profiling of ATL patients: compilation of disease related genes and evidence for TCF-4 involvement in BIRC5 gene expression and cell viability. Blood. 2009;113:4016–26.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Glimcher LH, Murphy KM. Lineage commitment in the immune system: the T helper lymphocyte grows up. Genes Dev. 2000;14(14):1693–711.PubMedGoogle Scholar
  77. 77.
    Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations. Annu Rev Immunol. 2010;28:445–89.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Kato K, Akashi K. Recent advances in therapeutic approaches for adult T-cell leukemia/lymphoma. Viruses. 2015;7(12):6604–12.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Yoshie O, Fujisawa R, Nakayama T, Harasawa H, Tago H, Izawa D, et al. Frequent expression of CCR4 in adult T-cell leukemia and human T-cell leukemia virus type 1-transformed T cells. Blood. 2002;99(5):1505–11.PubMedGoogle Scholar
  80. 80.
    Harasawa H, Yamada Y, Hieshima K, Jin Z, Nakayama T, Yoshie O, 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.PubMedGoogle Scholar
  81. 81.
    Choi J, Goh G, Walradt T, Hong BS, Bunick CG, Chen K, et al. Genomic landscape of cutaneous T cell lymphoma. Nat Genet. 2015;47(9):1011–9.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Damsky WE, Choi J. Genetics of cutaneous T cell lymphoma: from bench to bedside. Curr Treat Options in Oncol. 2016;17(7):33.Google Scholar
  83. 83.
    Huang Y, Su MW, Jiang X, Zhou Y. Evidence of an oncogenic role of aberrant TOX activation in cutaneous T-cell lymphoma. Blood. 2015;125(9):1435–43.PubMedGoogle Scholar
  84. 84.
    Dulmage BO, Akilov O, Vu JR, Falo LD, Geskin LJ. Dysregulation of the TOX-RUNX3 pathway in cutaneous T-cell lymphoma. Oncotarget 2015.  https://doi.org/10.18632/oncotarget.5742.
  85. 85.
    Haider A, Steininger A, Ullmann R, Hummel M, Dimitrova L, Beyer M, et al. Inactivation of RUNX3/p46 promotes cutaneous T-cell lymphoma. J Invest Dermatol. 2016;136(11):2287–96.PubMedGoogle Scholar
  86. 86.
    Ungewickell A, Bhaduri A, Rios E, Reuter J, Lee CS, Mah A, et al. Genomic analysis of mycosis fungoides and Sezary syndrome identifies recurrent alterations in TNFR2. Nat Genet. 2015;47(9):1056–60.PubMedGoogle Scholar
  87. 87.
    da Silva Almeida AC, Abate F, Khiabanian H, Martinez-Escala E, Guitart J, Tensen CP, et al. The mutational landscape of cutaneous T cell lymphoma and Sezary syndrome. Nat Genet. 2015;47(12):1465–70.PubMedPubMedCentralGoogle Scholar
  88. 88.
    Kiel MJ, Sahasrabuddhe AA, Rolland DC, et al. Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome. Nat Commun. 2015;6:8470.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Ichiyama K, Chen T, Wang X, Yan X, Kim BS, Tanaka S, et al. The methylcytosine dioxygenase Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells. Immunity. 2015;42(4):613–26.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Au WY, Weisenburger DD, Intragumtornchai T, Nakamura S, Kim WS, Sng I, et al. Clinical differences between nasal and extranasal natural killer/T-cell lymphoma: a study of 136 cases from the International Peripheral T-Cell Lymphoma Project. Blood. 2009;113(17):3931–7.PubMedGoogle Scholar
  91. 91.
    Kwong YL. The diagnosis and management of extranodal NK/T-cell lymphoma, nasal-type and aggressive NK-cell leukemia. J Clin Exp Hematop. 2011;51(1):21–8.PubMedGoogle Scholar
  92. 92.
    Coppo P, Gouilleux-Gruart V, Huang Y, Bouhlal H, Bouamar H, Bouchet S, et al. STAT3 transcription factor is constitutively activated and is oncogenic in nasal-type NK/T-cell lymphoma. Leukemia. 2009;23(9):1667–78.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Huang Y, de Leval L, Gaulard P. Molecular underpinning of extranodal NK/T-cell lymphoma. Best Pract Res Clin Haematol. 2013;26(1):57–74.PubMedGoogle Scholar
  94. 94.
    Huang Y, de Reynies A, de Leval L, Ghazi B, Martin-Garcia N, Travert M, et al. Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type. Blood. 2010;115(6):1226–37.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Iqbal J, Kucuk C, Deleeuw RJ, et al. Genomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killer-cell malignancies. Leukemia. 2009;23(6):1139–51.PubMedGoogle Scholar
  96. 96.
    Koo GC, Tan SY, Tang T, et al. Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma. Cancer Discov. 2012;2(7):591–7.PubMedGoogle Scholar
  97. 97.
    Bouchekioua A, Scourzic L, de Wever O, et al. JAK3 deregulation by activating mutations confers invasive growth advantage in extranodal nasal-type natural killer cell lymphoma. Leukemia. 2014;28(2):338–48.Google Scholar
  98. 98.
    Kimura H, Karube K, Ito Y, et al. Rare occurrence of JAK3 mutations in NK cell neoplasms in Japan. Leuk Lymphoma. 2013;1029–2403.  https://doi.org/10.3109/10428194.2013.819577.
  99. 99.
    Jiang L, Gu ZH, Yan ZX, et al. Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma. Nat Genet. 2015;47(9):1061–6.Google Scholar
  100. 100.
    Travert M, Huang Y, de Leval L, Martin-Garcia N, Delfau-Larue MH, Berger F, et al. Molecular features of hepatosplenic T-cell lymphoma unravels potential novel therapeutic targets. Blood. 2012;119(24):5795–806.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Belhadj K, Reyes F, Farcet JP, Tilly H, Bastard C, Angonin R, et al. Hepatosplenic gammadelta T-cell lymphoma is a rare clinicopathologic entity with poor outcome: report on a series of 21 patients. Blood. 2003;102(13):4261–9.PubMedGoogle Scholar
  102. 102.
    Delabie J, Holte H, Vose JM, Ullrich F, Jaffe ES, Savage KJ, et al. Enteropathy-associated T-cell lymphoma: clinical and histological findings from the international peripheral T-cell lymphoma project. Blood. 2011;118(1):148–55.PubMedGoogle Scholar
  103. 103.
    Lee MY, Tsou MH, Tan TD, Lu MC. Clinicopathological analysis of T-cell lymphoma in Taiwan according to WHO classification: high incidence of enteropathy-type intestinal T-cell lymphoma. Eur J Haematol. 2005;75(3):221–6.PubMedGoogle Scholar
  104. 104.
    Verbeek WH, Van De Water JM, Al-Toma A, Oudejans JJ, Mulder CJ, Coupe VM. Incidence of enteropathy-associated T-cell lymphoma: a nation-wide study of a population-based registry in the Netherlands. Scand J Gastroenterol. 2008;43(11):1322–8.PubMedGoogle Scholar
  105. 105.
    Moffitt AB, Ondrejka SL, McKinney M, Rempel RE, Goodlad JR, Teh CH, et al. Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2. J Exp Med. 2017;214:1371–86.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Sato F, Ishida T, Ito A, Mori F, Masaki A, Takino H, et al. Angioimmunoblastic T-cell lymphoma mice model. Leuk Res. 2013;37(1):21–7.PubMedGoogle Scholar
  107. 107.
    Felsher DW, Bishop JM. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol Cell. 1999;4(2):199–207.PubMedGoogle Scholar
  108. 108.
    Liu G, Parant JM, Lang G, Chau P, Chavez-Reyes A, el-Naggar AK, et al. Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice. Nat Genet. 2004;36(1):63–8.PubMedGoogle Scholar
  109. 109.
    Donehower LA, Harvey M, Vogel H, McArthur MJ, Montgomery CA, Park SH, et al. Effects of genetic background on tumorigenesis in p53-deficient mice. Mol Carcinog. 1995;14(1):16–22.PubMedGoogle Scholar
  110. 110.
    Kamijo T, Bodner S, van de Kamp E, Randle DH, Sherr CJ. Tumor spectrum in ARF-deficient mice. Cancer Res. 1999;59(9):2217–22.PubMedGoogle Scholar
  111. 111.
    Suzuki A, de la Pompa JL, Stambolic V, Elia AJ, Sasaki T, Barrantes IB, et al. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol. 1998;8(21):1169–78.PubMedGoogle Scholar
  112. 112.
    Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M, Yamada KM, et al. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci U S A. 1999;96(4):1563–8.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Canela A, Martin-Caballero J, Flores JM, Blasco MA. Constitutive expression of tert in thymocytes leads to increased incidence and dissemination of T-cell lymphoma in Lck-Tert mice. Mol Cell Biol. 2004;24(10):4275–93.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Suzuki A, Yamaguchi MT, Ohteki T, Sasaki T, Kaisho T, Kimura Y, et al. T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity. 2001;14(5):523–34.PubMedGoogle Scholar
  115. 115.
    Hagenbeek TJ, Spits H. T-cell lymphomas in T-cell-specific Pten-deficient mice originate in the thymus. Leukemia. 2008;22(3):608–19.PubMedGoogle Scholar
  116. 116.
    Cutucache CE, Herek TA. Burrowing through the heterogeneity: review of mouse models of PTCL-NOS. Front Oncol. 2016;6:206.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Haney SL, Upchurch GM, Opavska J, Klinkebiel D, Appiah AK, Smith LM, et al. Loss of Dnmt3a induces CLL and PTCL with distinct methylomes and transcriptomes in mice. Sci Rep. 2016;6:34222.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Solary E, Bernard OA, Tefferi A, Fuks F, Vainchenker W. The ten-eleven translocation-2 (TET2) gene in hematopoiesis and hematopoietic diseases. Leukemia. 2014;28(3):485–96.PubMedGoogle Scholar
  119. 119.
    Muto H, Sakata-Yanagimoto M, Nagae G, et al. Reduced TET2 function leads to T-cell lymphoma with follicular helper T-cell-like features in mice. Blood Cancer J. 2014;4:e264.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Bachy E, Urb M, Chandra S, Robinot R, Bricard G, de Bernard S, et al. CD1d-restricted peripheral T cell lymphoma in mice and humans. J Exp Med. 2016;213(5):841–57.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Shultz LD, Ishikawa F, Greiner DL. Humanized mice in translational biomedical research. Nat Rev Immunol. 2007;7(2):118–30.PubMedGoogle Scholar
  122. 122.
    Ito M, Hiramatsu H, Kobayashi K, Suzue K, Kawahata M, Hioki K, et al. NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood. 2002;100(9):3175–82.PubMedGoogle Scholar
  123. 123.
    Hutmacher DW, Cukierman E. Engineering of tumor microenvironments. Adv Drug Deliv Rev. 2014;79-80:1–2.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Waseem Lone
    • 1
  • Aisha Alkhiniji
    • 1
  • Jayadev Manikkam Umakanthan
    • 2
  • Javeed Iqbal
    • 1
  1. 1.Department of Pathology and MicrobiologyUniversity of Nebraska Medical CenterOmahaUSA
  2. 2.Department of Internal Medicine, Division of Oncology & HematologyUniversity of Nebraska Medical CenterOmahaUSA

Personalised recommendations