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Molecular and Genomic Landscape of Peripheral T-Cell Lymphoma

  • Javeed Iqbal
  • Catalina Amador
  • Timothy W. McKeithan
  • Wing C. ChanEmail author
Chapter
Part of the Cancer Treatment and Research book series (CTAR, volume 176)

Abstract

Peripheral T-cell lymphoma (PTCL) is an uncommon group of lymphoma covering a diverse spectrum of entities. Little was known regarding the molecular and genomic landscapes of these diseases until recently but the knowledge is still quite spotty with many rarer types of PTCL remain largely unexplored. In this chapter, the recent findings from gene expression profiling (GEP) studies, including profiling data on microRNA, where available, will be presented with emphasis on the implication on molecular diagnosis, prognostication, and the identification of new entities (PTCL-GATA3 and PTCL-TBX21) in the PTCL-NOS group. Recent studies using next-generation sequencing have unraveled the mutational landscape in a number of PTCL entities leading to a marked improvement in the understanding of their pathogenesis and biology. While many mutations are shared among PTCL entities, the frequency varies and certain mutations are quite unique to a specific entity. For example, TET2 is often mutated but this is particularly frequent (70-80%) in angioimmunoblastic T-cell lymphoma (AITL) and IDH2 R172 mutations appear to be unique for AITL. In general, chromatin modifiers and molecular components in the CD28/T-cell receptor signaling pathways are frequently mutated. The major findings will be summarized in this chapter correlating with GEP data and clinical features where appropriate. The mutational landscape of cutaneous T-cell lymphoma, specifically on mycosis fungoides and Sezary syndrome, will also be discussed.

Keywords

Peripheral T-cell lymphoma Gene expression profiling Mutational landscape Pathogenesis Biology Mycosis fungoides Sezary syndrome 

References

  1. 1.
    Rudiger T, Weisenburger DD, Anderson JR et al (2002) Peripheral T-cell lymphoma (excluding anaplastic large-cell lymphoma): results from the Non-Hodgkin’s Lymphoma Classification Project. Ann Oncol 13(1):140–149PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Swerdlow SH, Campo E, Pileri SA et al (2016) The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 127(20):2375–2390PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Swerdlow SH, Campo E, Harris NL et al (2008) WHO classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th ednGoogle Scholar
  4. 4.
    Bellei M, Chiattone CS, Luminari S et al (2012) T-cell lymphomas in South america and europe. Rev Bras Hematol Hemoter. 34(1):42–47PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Arora N, Manipadam MT, Nair S (2013) 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 54(5):1004–1011PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Perry AM, Diebold J, Nathwani BN et al (2016) Non-Hodgkin lymphoma in the Far East: review of 730 cases from the international non-Hodgkin lymphoma classification project. Ann Hematol 95(2):245–251PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    International peripheral T-cell and natural killer/t-cell lymphoma study (2008) pathology findings and clinical outcomes. J Clin Oncol 26(25):4124–4130CrossRefGoogle Scholar
  8. 8.
    Perry AM, Diebold J, Nathwani BN et al (2016) Non-Hodgkin lymphoma in the developing world: review of 4539 cases from the International Non-Hodgkin Lymphoma Classification Project. Haematologica 101(10):1244–1250PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Adams SV, Newcomb PA, Shustov AR (2016) Racial Patterns of Peripheral T-Cell Lymphoma Incidence and Survival in the United States. J Clin Oncol 34(9):963–971PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Wang. SS, Vose. JM (2103) Epidemiology and Prognosis of T-Cell Lymphoma. Springer Science, New YorkGoogle Scholar
  11. 11.
    Iqbal J, Wright G, Wang C et al (2014) Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma. Blood 123(19):2915–2923PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Iqbal J, Weisenburger DD, Greiner TC et al (2010) Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma. Blood 115(5):1026–1036PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Iqbal J, Weisenburger DD, Chowdhury A et al (2011) 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 25(2):348–358PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Xu B, Liu P (2014) No survival improvement for patients with angioimmunoblastic T-cell lymphoma over the past two decades: a population-based study of 1207 cases. PLoS ONE 9(3):e92585PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Croziera JA,, Shera T, Yangb D et al (2015) 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 LeukemiaGoogle Scholar
  16. 16.
    Briski R, Feldman AL, Bailey NG et al (2014) The role of front-line anthracycline-containing chemotherapy regimens in peripheral T-cell lymphomas. Blood Cancer J. 4:e214PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Swerdlow SH, Elias Campo, Harris NL et al (2017) WHO classification of Tumours of the Haematopoitic and Lymphoid Tissues. Lyon, IARC Press, FranceGoogle Scholar
  18. 18.
    Germain RN (2002) T-cell development and the CD4-CD8 lineage decision. Nat Rev Immunol 2(5):309–322PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Martin CH, Aifantis I, Scimone ML et al (2003) Efficient thymic immigration of B220+ lymphoid-restricted bone marrow cells with T precursor potential. Nat Immunol 4(9):866–873PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Poltorak M, Meinert I, Stone JC, Schraven B, Simeoni L (2014) Sos1 regulates sustained TCR-mediated Erk activation. Eur J Immunol 44(5):1535–1540PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Filipp D, Zhang J, Leung BL et al (2003) Regulation of Fyn through translocation of activated Lck into lipid rafts. J Exp Med 197(9):1221–1227PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Sugie K, Jeon MS, Grey HM (2004) Activation of naive CD4 T cells by anti-CD3 reveals an important role for Fyn in Lck-mediated signaling. Proc Natl Acad Sci U S A. 101(41):14859–14864PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Cannons JL, Yu LJ, Hill B et al (2004) SAP regulates T(H)2 differentiation and PKC-theta-mediated activation of NF-kappaB1. Immunity 21(5):693–706PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Cannons JL, Qi H, Lu KT et al (2010) Optimal germinal center responses require a multistage T cell: B cell adhesion process involving integrins, SLAM-associated protein, and CD84. Immunity 32(2):253–265PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Latour S, Roncagalli R, Chen R et al (2003) Binding of SAP SH2 domain to FynT SH3 domain reveals a novel mechanism of receptor signalling in immune regulation. Nat Cell Biol 5(2):149–154PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Yasuda K, Nagafuku M, Shima T et al (2002) Cutting edge: Fyn is essential for tyrosine phosphorylation of Csk-binding protein/phosphoprotein associated with glycolipid-enriched microdomains in lipid rafts in resting T cells. J Immunol. 169(6):2813–2817PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Kong KF, Yokosuka T, Canonigo-Balancio AJ, Isakov N, Saito T, Altman A (2011) A motif in the V3 domain of the kinase PKC-theta determines its localization in the immunological synapse and functions in T cells via association with CD28. Nat Immunol 12(11):1105–1112PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Kang JA, Choi H, Yang T, Cho SK, Park ZY, Park SG (2017) PKCtheta-Mediated PDK1 Phosphorylation Enhances T Cell Activation by Increasing PDK1 Stability. Mol Cells 40(1):37–44PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Qiao Q, Yang C, Zheng C et al (2013) Structural architecture of the CARMA1/Bcl10/MALT1 signalosome: nucleation-induced filamentous assembly. Mol Cell 51(6):766–779PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Isakov N, Altman A (2002) Protein kinase C(theta) in T cell activation. Annu Rev Immunol 20:761–794PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Gazzola A, Mannu C, Rossi M et al (2014) The evolution of clonality testing in the diagnosis and monitoring of hematological malignancies. Ther Adv Hematol. 5(2):35–47PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    van Dongen JJ, Langerak AW, Bruggemann M et al (2003) Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia 17(12):2257–2317PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Szczepanski T, van der Velden VH, Raff T et al (2003) Comparative analysis of T-cell receptor gene rearrangements at diagnosis and relapse of T-cell acute lymphoblastic leukemia (T-ALL) shows high stability of clonal markers for monitoring of minimal residual disease and reveals the occurrence of second T-ALL. Leukemia 17(11):2149–2156PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Iqbal J, Naushad H, Bi C et al (2016) Genomic signatures in B-cell lymphoma: How can these improve precision in diagnosis and inform prognosis? Blood Rev 30(2):73–88PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Iqbal J, Wilcox R, Naushad H et al (2016) Genomic signatures in T-cell lymphoma: How can these improve precision in diagnosis and inform prognosis? Blood Rev 30(2):89–100CrossRefGoogle Scholar
  36. 36.
    Iqbal J, Shen Y, Huang X et al (2015) Global microRNA expression profiling uncovers molecular markers for classification and prognosis in aggressive B-cell lymphoma. Blood 125(7):1137–1145PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Iqbal J, Shen Y, Liu Y et al (2012) Genome-wide miRNA profiling of mantle cell lymphoma reveals a distinct subgroup with poor prognosis. Blood 119(21):4939–4948PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Liu C, Iqbal J, Teruya-Feldstein J et al (2013) MicroRNA expression profiling identifies molecular signatures associated with anaplastic large cell lymphoma. Blood 122(12):2083–2092PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Bouska A, McKeithan TW, Deffenbacher KE et al (2014) Genome-wide copy-number analyses reveal genomic abnormalities involved in transformation of follicular lymphoma. Blood 123(11):1681–1690PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Bouska A, Zhang W, Gong Q et al (2017) Combined copy number and mutation analysis identifies oncogenic pathways associated with transformation of follicular lymphoma. Leukemia 31(1):83–91PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Cairns RA, Iqbal J, Lemonnier F et al (2012) IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. Blood 119(8):1901–1903PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Guo S, Chan JK, Iqbal J et al (2014) EZH2 mutations in follicular lymphoma from different ethnic groups and associated gene expression alterations. Clin Cancer Res 20(12):3078–3086PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Kucuk C, Hu X, Jiang B et al (2015) Global promoter methylation analysis reveals novel candidate tumor suppressor genes in natural killer cell lymphoma. Clin Cancer Res 21(7):1699–1711PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    McKinney M, Moffitt AB, Gaulard P et al (2017) The Genetic Basis of Hepatosplenic T-cell Lymphoma. Cancer Discov 7(4):369–379PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Laurent C et al (2017) J Clinic Oncol 35(18):2008–2017Google Scholar
  46. 46.
    Weisenburger et al (2011) Blood, 117:3402–3408Google Scholar
  47. 47.
    Bowen et al (2014) Bristish J Hematol 166:202–208Google Scholar
  48. 48.
    de Leval L, Rickman DS, Thielen C et al (2007) 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 109(11):4952–4963PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Martinez-Delgado B (2006) Peripheral T-cell lymphoma gene expression profiles. Hematol Oncol 24(3):113–119PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Piccaluga PP, Agostinelli C, Califano A et al (2007) Gene expression analysis of peripheral T cell lymphoma, unspecified, reveals distinct profiles and new potential therapeutic targets. J Clin Invest. 117(3):823–834PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Cuadros M, Dave SS, Jaffe ES et al (2007) Identification of a proliferation signature related to survival in nodal peripheral T-cell lymphomas. J Clin Oncol 25(22):3321–3329PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Martinez-Delgado B, Cuadros M, Honrado E et al (2005) Differential expression of NF-kappaB pathway genes among peripheral T-cell lymphomas. Leukemia 19(12):2254–2263PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Piccaluga PP, Fuligni F, De Leo A et al (2013) Molecular profiling improves classification and prognostication of nodal peripheral T-cell lymphomas: results of a phase III diagnostic accuracy study. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 31(24):3019–3025CrossRefGoogle Scholar
  54. 54.
    Ballester B, Ramuz O, Gisselbrecht C et al (2006) Gene expression profiling identifies molecular subgroups among nodal peripheral T-cell lymphomas. Oncogene 25(10):1560–1570PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    O’Shea JJ, Paul WE (2010) Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327(5969):1098–1102PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Wang T, Feldman AL, Wada DA et al (2014) GATA-3 expression identifies a high-risk subset of PTCL, NOS with distinct molecular and clinical features. Blood 123(19):3007–3015PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Heavican TB, Yu J, Bouska A, Greiner TC, Lachel CM, Wang C, Dave BJ, Amador CC, Fu K, Vose JM, Weisenburger DD, Gascoyne RD, Hartmann S, Pedersen MBJ, Wilcox R, Teh BT, Lim ST, Ong CK, Seto M, Berger F, Rosenwald A, Ott G, Campo E, Rimsza LM, Jaffe ES, Braziel RM, d’Amore FA, Inghirami G, Bertoni F, Staudt L, McKeithan TW, Pileri SA, Chan WC, Iqbal J (2016) Molecular subgroups of peripheral T-cell lymphoma evolve by distinct genetic pathways. In: 58th ASH Annual Meeting and Exposition, San Diego, CAGoogle Scholar
  58. 58.
    Schatz JH, Horwitz SM, Teruya-Feldstein J et al (2015) Targeted mutational profiling of peripheral T-cell lymphoma not otherwise specified highlights new mechanisms in a heterogeneous pathogenesis. Leukemia 29(1):237–241PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Abate F, da Silva-Almeida AC, Zairis S et al (2017) Activating mutations and translocations in the guanine exchange factor VAV1 in peripheral T-cell lymphomas. Proc Natl Acad Sci U S A. 114(4):764–769PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Yoo HY, Sung MK, Lee SH et al (2014) A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma. Nat Genet 46(4):371–375PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Laginestra MA, Piccaluga PP, Fuligni F et al (2014) Pathogenetic and diagnostic significance of microRNA deregulation in peripheral T-cell lymphoma not otherwise specified. Blood Cancer J. 4:259PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Dobay MP, Lemonnier F, Missiaglia E et al (2017) Integrative clinicopathological and molecular analyses of angioimmunoblastic T-cell lymphoma and other nodal lymphomas of follicular helper T-cell origin. Haematologica 102(4):e148–e151PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Piccaluga et al (2007) Cancer Res 15, 67(22):10703–10710PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Crotty S (2014) Immunity 41(4):529–542PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Fazilleau N, McHeyzer-Williams LJ, Rosen H, McHeyzer-Williams MG (2009) The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding. Nat Immunol 10(4):375–384PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Hatzi K, Nance JP, Kroenke MA et al (2015) BCL6 orchestrates Tfh cell differentiation via multiple distinct mechanisms. J Exp Med 212(4):539–553PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Dupuis J, Boye K, Martin N et al (2006) Expression of CXCL13 by neoplastic cells in angioimmunoblastic T-cell lymphoma (AITL): a new diagnostic marker providing evidence that AITL derives from follicular helper T cells. Am J Surg Pathol 30(4):490–494PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Miysohi et al (2012) Am J Clin Pathol 137(6):879–89Google Scholar
  69. 69.
    Bisig B, Thielen C, Herens C et al (2012) c-Maf expression in angioimmunoblastic T-cell lymphoma reflects follicular helper T-cell derivation rather than oncogenesis. Histopathology 60(2):371–376PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Murakami YI, Yatabe Y, Sakaguchi T et al (2007) c-Maf expression in angioimmunoblastic T-cell lymphoma. Am J Surg Pathol 31(11):1695–1702PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Iqbal J et al (2007) Leukemia 21(11):2332–2343Google Scholar
  72. 72.
    Iqbal J, Weisenburger DD, Greiner TC et al (2010) Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma. Blood 115(5):1026–1036PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Grogg KL, Attygalle AD, Macon WR, Remstein ED, Kurtin PJ, Dogan A (2005) Angioimmunoblastic T-cell lymphoma: a neoplasm of germinal-center T-helper cells? Blood 106(4):1501–1502PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Schlegelberger B, Himmler A, Godde E, Grote W, Feller AC, Lennert K (1994) Cytogenetic findings in peripheral T-cell lymphomas as a basis for distinguishing low-grade and high-grade lymphomas. Blood 83(2):505–511PubMedPubMedCentralGoogle Scholar
  75. 75.
    Nelson M, Horsman DE, Weisenburger DD et al (2008) Cytogenetic abnormalities and clinical correlations in peripheral T-cell lymphoma. Br J Haematol 141(4):461–469PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Lepretre S, Buchonnet G, Stamatoullas A et al (2000) Chromosome abnormalities in peripheral T-cell lymphoma. Cancer Genet Cytogenet 117(1):71–79PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Lakkala-Paranko T, Franssila K, Lappalainen K et al (1987) Chromosome abnormalities in peripheral T-cell lymphoma. Br J Haematol 66(4):451–460PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Lemonnier F, Couronne L, Parrens M et al (2012) Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters. Blood 120(7):1466–1469PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Sakata-Yanagimoto M, Enami T, Yoshida K et al (2014) Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat Genet 46(2):171–175CrossRefGoogle Scholar
  80. 80.
    Odejide O, Weigert O, Lane AA et al (2014) A targeted mutational landscape of angioimmunoblastic T-cell lymphoma. Blood 123(9):1293–1296PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Dawlaty MM, Ganz K, Powell BE, et al Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development. Cell Stem Cell 9(2):166–175PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Dawlaty MM, Breiling A, Le T, et al. Combined deficiency of Tet1 and Tet2 causes epigenetic abnormalities but is compatible with postnatal development. Dev Cell 24(3):310–323PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Wu H, Zhang Y (2011) Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes Dev 25(23):2436–2452PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Hill PW, Amouroux R, Hajkova P (2014) DNA demethylation, Tet proteins and 5-hydroxymethylcytosine in epigenetic reprogramming: an emerging complex story. Genomics 104(5):324–333PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Losman JA, Looper RE, Koivunen P et al (2013) (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 339(6127):1621–1625CrossRefGoogle Scholar
  86. 86.
    Koivunen P, Lee S, Duncan CG et al (2012) Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 483(7390):484–488PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Li Z, Cai X, Cai CL et al (2011) Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood 118(17):4509–4518PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Sasaki M, Knobbe CB, Munger JC et al (2012) IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488(7413):656–659PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Akbay EA, Moslehi J, Christensen CL et al (2014) D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice. Genes Dev 28(5):479–490PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Chen C, Liu Y, Lu C et al (2013) Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition. Genes Dev 27(18):1974–1985PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Xu W, Yang H, Liu Y et al Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 19(1):17–30Google Scholar
  92. 92.
    Palomero T, Couronne L, Khiabanian H et al Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nature genetics 46(2):166–170PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Nagata Y, Kontani K, Enami T et al (2016) Variegated RHOA mutations in adult T-cell leukemia/lymphoma. Blood 127(5):596–604PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Yoo HY, Sung MK, Lee SH, et al A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma. Nature genetics 46(4):371–375PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Abdel-Wahab O, Levine RL (2013) Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia. Blood 121(18):3563–3572PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Rohr J, Guo S, Hu D et al (2014) CD28 Mutations in Peripheral T-Cell Lymphomagenesis and Progression. Blood 124(21):1681–1681Google Scholar
  97. 97.
    Rohr J, Guo S, Huo J et al (2015) Recurrent activating mutations of CD28 in peripheral T-cell lymphomas. LeukemiaGoogle Scholar
  98. 98.
    Wang C, McKeithan TW, Gong Q et al (2015) IDH2R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma. Blood 126(15):1741–1752PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    DiNardo CD, Propert KJ, Loren AW et al Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia. Blood 121(24):4917–4924PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Cheminant M, Bruneau J, Kosmider O et al (2014) Efficacy of 5-Azacytidine in a TET2 mutated angioimmunoblastic T cell lymphoma. Br J HaematolGoogle Scholar
  101. 101.
    Pro B, Horwitz SM, Prince HM et al (2016) Romidepsin induces durable responses in patients with relapsed or refractory angioimmunoblastic T-cell lymphoma. Hematol OncolGoogle Scholar
  102. 102.
    Borroto A, Gil D, Delgado P et al (2000) Rho regulates T cell receptor ITAM-induced lymphocyte spreading in an integrin-independent manner. Eur J Immunol 30(12):3403–3410PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Rougerie P, Delon J Rho GTPases: masters of T lymphocyte migration and activation. Immunol Lett 142(1–2):1-13PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Cleverley SC, Costello PS, Henning SW, Cantrell DA (2000) Loss of Rho function in the thymus is accompanied by the development of thymic lymphoma. Oncogene 19(1):13–20PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Cortes JR, Ambesi-Impiombato A, Couronne L, Kim CS, West Z, Belver L, da Silva Almeida AC, Bhagat G, Bernard OA, Ferrando AA, PalomeroT (2016) Role and Mechanisms of Rhoa G17 V in the Pathogenesis of AITL. ASH Meeting, San DiegoGoogle Scholar
  106. 106.
    Li Z, Dong X, Wang Z et al (2005) Regulation of PTEN by Rho small GTPases. Nat Cell Biol 7(4):399–404PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Morris SW, Kirstein MN, Valentine MB et al (1995) Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 267(5196):316–317PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Mason DY, Bastard C, Rimokh R et al (1990) CD30-positive large cell lymphomas (‘Ki-1 lymphoma’) are associated with a chromosomal translocation involving 5q35. Br J Haematol 74(2):161–168PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Morris SW, Kirstein MN, Valentine MB et al (1994) Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 263(5151):1281–1284PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Rimokh R, Magaud JP, Berger F et al (1989) A translocation involving a specific breakpoint (q35) on chromosome 5 is characteristic of anaplastic large cell lymphoma (‘Ki-1 lymphoma’). Br J Haematol 71(1):31–36PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Agnelli L, Mereu E, Pellegrino E et al (2012) Identification of a 3-gene model as a powerful diagnostic tool for the recognition of ALK-negative anaplastic large-cell lymphoma. Blood 120(6):1274–1281PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Piva R, Pellegrino E, Mattioli M et al (2006) Functional validation of the anaplastic lymphoma kinase signature identifies CEBPB and BCL2A1 as critical target genes. J Clin Invest. 116(12):3171–3182PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Matsuyama H, Suzuki HI, Nishimori H et al (2011) miR-135b mediates NPM-ALK-driven oncogenicity and renders IL-17-producing immunophenotype to anaplastic large cell lymphoma. Blood 118(26):6881–6892PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Abate F, Todaro M, van der Krogt JA et al (2014) A novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation. LeukemiaGoogle Scholar
  115. 115.
    Parrilla Castellar ER, Jaffe ES, Said JW et al (2014) ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. Blood 124(9):1473–1480PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Crescenzo R, Abate F, Lasorsa E et al (2015) Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell 27(4):516–532PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Chiarle R, Voena C, Ambrogio C, Piva R, Inghirami G (2008) The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer 8(1):11–23PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Spaccarotella E, Pellegrino E, Ferracin M et al (2014) STAT3-mediated activation of microRNA cluster 17–92 promotes proliferation and survival of ALK-positive anaplastic large cell lymphoma. Haematologica 99(1):116–124PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Merkel O, Hamacher F, Laimer D et al (2010) Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)+ and ALK- anaplastic large-cell lymphoma. Proc Natl Acad Sci U S A. 107(37):16228–16233PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Portis T, Grossman WJ, Harding JC, Hess JL, Ratner L (2001) Analysis of p53 inactivation in a human T-cell leukemia virus type 1 Tax transgenic mouse model. J Virol 75(5):2185–2193PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Vernin C, Thenoz M, Pinatel C et al (2014) HTLV-1 bZIP factor HBZ promotes cell proliferation and genetic instability by activating OncomiRs. Cancer Res 74(21):6082–6093PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Wright DG, Marchal C, Hoang K et al (2016) Human T-cell leukemia virus type-1-encoded protein HBZ represses p53 function by inhibiting the acetyltransferase activity of p300/CBP and HBO1. Oncotarget. 7(2):1687–1706PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    Sasaki H, Nishikata I, Shiraga T et al (2005) Overexpression of a cell adhesion molecule, TSLC1, as a possible molecular marker for acute-type adult T-cell leukemia. Blood 105(3):1204–1213PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Pise-Masison CA, Radonovich M, Dohoney K et al (2009) Gene expression profiling of ATL patients: compilation of disease related genes and evidence for TCF-4 involvement in BIRC5 gene expression and cell viability. BloodGoogle Scholar
  125. 125.
    Zinzani et al (2016) Haematologica 101(10):e407–410PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Ogura M et al (2014) J Clin Oncol 10, 32(11):1157–1163Google Scholar
  127. 127.
    Kataoka K, Nagata Y, Kitanaka A et al (2015) Integrated molecular analysis of adult T cell leukemia/lymphoma. Nat Genet 47(11):1304–1315CrossRefGoogle Scholar
  128. 128.
    Yoshie O, Fujisawa R, Nakayama T et al (2002) Frequent expression of CCR4 in adult T-cell leukemia and human T-cell leukemia virus type 1-transformed T cells. Blood 99(5):1505–1511PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Harasawa H, Yamada Y, Hieshima K et al (2006) Survey of chemokine receptor expression reveals frequent co-expression of skin-homing CCR4 and CCR10 in adult T-cell leukemia/lymphoma. Leuk Lymphoma 47(10):2163–2173PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Li J, Lu E, Yi T, Cyster JG (2016) EBI2 augments Tfh cell fate by promoting interaction with IL-2-quenching dendritic cells. Nature 533(7601):110–114PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Fujii K, Ishimaru F, Nakase K et al (2003) Over-expression of short isoforms of Helios in patients with adult T-cell leukaemia/lymphoma. Br J Haematol 120(6):986–989PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Zhang Z, Swindle CS, Bates JT, Ko R, Cotta CV, Klug CA (2007) Expression of a non-DNA-binding isoform of Helios induces T-cell lymphoma in mice. Blood 109(5):2190–2197PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Sato H, Oka T, Shinnou Y et al (2010) Multi-step aberrant CpG island hyper-methylation is associated with the progression of adult T-cell leukemia/lymphoma. Am J Pathol 176(1):402–415PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Nosaka K, Maeda M, Tamiya S, Sakai T, Mitsuya H, Matsuoka M (2000) Increasing methylation of the CDKN2A gene is associated with the progression of adult T-cell leukemia. Cancer Res 60(4):1043–1048PubMedPubMedCentralGoogle Scholar
  135. 135.
    Fujikawa D, Nakagawa S, Hori M et al (2016) Polycomb-dependent epigenetic landscape in adult T-cell leukemia. Blood 127(14):1790–1802CrossRefGoogle Scholar
  136. 136.
    Krejsgaard T, Lindahl LM, Mongan NP et al (2016) Malignant inflammation in cutaneous T-cell lymphoma—a hostile takeover. Seminars in immunopathologyGoogle Scholar
  137. 137.
    Macias ES, Pereira FA, Rietkerk W, Safai B (2011) Superantigens in dermatology. J Am Acad Dermatol 64(3):455–472; Quiz 473–454PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Suga H, Sugaya M, Miyagaki T et al (2014) Skin barrier dysfunction and low antimicrobial peptide expression in cutaneous T-cell lymphoma. Clin Cancer Res 20(16):4339–4348PubMedCrossRefPubMedCentralGoogle Scholar
  139. 139.
    Thode C, Woetmann A, Wandall HH et al (2015) Malignant T cells secrete galectins and induce epidermal hyperproliferation and disorganized stratification in a skin model of cutaneous T-cell lymphoma. J Invest Dermatol. 135(1):238–246PubMedCrossRefPubMedCentralGoogle Scholar
  140. 140.
    Dobbeling U, Dummer R, Laine E, Potoczna N, Qin JZ, Burg G (1998) Interleukin-15 is an autocrine/paracrine viability factor for cutaneous T-cell lymphoma cells. Blood 92(1):252–258PubMedGoogle Scholar
  141. 141.
    Leroy S, Dubois S, Tenaud I et al (2001) Interleukin-15 expression in cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome). The British journal of dermatology. 144(5):1016–1023PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Netchiporouk E, Litvinov IV, Moreau L, Gilbert M, Sasseville D, Duvic M (2014) Deregulation in STAT signaling is important for cutaneous T-cell lymphoma (CTCL) pathogenesis and cancer progression. Cell Cycle 13(21):3331–3335PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Mishra A, La Perle K, Kwiatkowski S et al (2016) Mechanism, Consequences, and Therapeutic Targeting of Abnormal IL15 Signaling in Cutaneous T-cell Lymphoma. Cancer Discov 6(9):986–1005PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    McKenzie RC, Jones CL, Tosi I, Caesar JA, Whittaker SJ, Mitchell TJ (2012) Constitutive activation of STAT3 in Sezary syndrome is independent of SHP-1. Leukemia 26(2):323–331PubMedCrossRefPubMedCentralGoogle Scholar
  145. 145.
    van der Fits L, Out-Luiting JJ, van Leeuwen MA et al (2012) Autocrine IL-21 stimulation is involved in the maintenance of constitutive STAT3 activation in Sezary syndrome. J Invest Dermatol. 132(2):440–447PubMedCrossRefPubMedCentralGoogle Scholar
  146. 146.
    Takahashi N, Sugaya M, Suga H et al (2016) Thymic Stromal Chemokine TSLP Acts through Th2 Cytokine Production to Induce Cutaneous T-cell Lymphoma. Cancer Res 76(21):6241–6252PubMedCrossRefGoogle Scholar
  147. 147.
    Tuzova M, Richmond J, Wolpowitz D et al (2015) CCR4+ T cell recruitment to the skin in mycosis fungoides: potential contributions by thymic stromal lymphopoietin and interleukin-16. Leuk Lymphoma 56(2):440–449PubMedCrossRefPubMedCentralGoogle Scholar
  148. 148.
    Geskin LJ, Viragova S, Stolz DB, Fuschiotti P (2015) Interleukin-13 is overexpressed in cutaneous T-cell lymphoma cells and regulates their proliferation. Blood 125(18):2798–2805PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Ohmatsu H, Humme D, Gulati N et al (2014) IL32 is progressively expressed in mycosis fungoides independent of helper T-cell 2 and helper T-cell 9 polarization. Cancer Immunol Res 2(9):890–900PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Suga H, Sugaya M, Miyagaki T et al (2014) The role of IL-32 in cutaneous T-cell lymphoma. J Invest Dermatol. 134(5):1428–1435PubMedCrossRefPubMedCentralGoogle Scholar
  151. 151.
    Lauenborg B, Christensen L, Ralfkiaer U et al (2015) Malignant T cells express lymphotoxin alpha and drive endothelial activation in cutaneous T cell lymphoma. Oncotarget. 6(17):15235–15249PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Michel L, Jean-Louis F, Begue E, Bensussan A, Bagot M (2013) Use of PLS3, Twist, CD158 k/KIR3DL2, and NKp46 gene expression combination for reliable Sezary syndrome diagnosis. Blood 121(8):1477–1478PubMedCrossRefPubMedCentralGoogle Scholar
  153. 153.
    Wong HK, Gibson H, Hake T et al (2015) Promoter-Specific Hypomethylation Is Associated with Overexpression of PLS3, GATA6, and TWIST1 in the Sezary Syndrome. J Invest Dermatol. 135(8):2084–2092PubMedCrossRefGoogle Scholar
  154. 154.
    Huang Y, Su MW, Jiang X, Zhou Y (2015) Evidence of an oncogenic role of aberrant TOX activation in cutaneous T-cell lymphoma. Blood 125(9):1435–1443PubMedCrossRefGoogle Scholar
  155. 155.
    Dulmage BO, Akilov O, Vu JR, Falo LD, Geskin LJ (2015) Dysregulation of the TOX-RUNX3 pathway in cutaneous T-cell lymphoma. OncotargetGoogle Scholar
  156. 156.
    Haider A, Steininger A, Ullmann R et al (2016) Inactivation of RUNX3/p46 Promotes Cutaneous T-Cell Lymphoma. J Invest Dermatol. 136(11):2287–2296PubMedCrossRefPubMedCentralGoogle Scholar
  157. 157.
    Choi J, Goh G, Walradt T et al (2015) Genomic landscape of cutaneous T cell lymphoma. Nat Genet 47(9):1011–1019PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    da Silva Almeida AC, Abate F, Khiabanian H et al (2015) The mutational landscape of cutaneous T cell lymphoma and Sezary syndrome. Nat Genet 47(12):1465–1470PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Kiel MJ, Sahasrabuddhe AA, Rolland DC et al (2015) Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome. Nat Commun. 6:8470PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Wang L, Ni X, Covington KR et al (2015) Genomic profiling of Sezary syndrome identifies alterations of key T cell signaling and differentiation genes. Nat Genet 47(12):1426–1434PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Mathur R, Alver BH, San Roman AK et al (2017) ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. Nat Genet 49(2):296–302PubMedCrossRefPubMedCentralGoogle Scholar
  162. 162.
    Watanabe R, Ui A, Kanno S et al (2014) SWI/SNF factors required for cellular resistance to DNA damage include ARID1A and ARID1B and show interdependent protein stability. Cancer Res 74(9):2465–2475PubMedCrossRefPubMedCentralGoogle Scholar
  163. 163.
    Williamson CT, Miller R, Pemberton HN et al (2016) ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A. Nat Commun. 7:13837PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Guo C, Chen LH, Huang Y et al (2013) KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation. Oncotarget. 4(11):2144–2153PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Kaikkonen MU, Spann NJ, Heinz S et al (2013) Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. Mol Cell 51(3):310–325PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Hidaka T, Nakahata S, Hatakeyama K et al (2008) Down-regulation of TCF8 is involved in the leukemogenesis of adult T-cell leukemia/lymphoma. Blood 112(2):383–393PubMedCrossRefGoogle Scholar
  167. 167.
    Papadopoulou V, Postigo A, Sanchez-Tillo E, Porter AC, Wagner SD (2010) ZEB1 and CtBP form a repressive complex at a distal promoter element of the BCL6 locus. Biochem J 427(3):541–550PubMedCrossRefGoogle Scholar
  168. 168.
    Wang J, Lee S, Teh CE, Bunting K, Ma L, Shannon MF (2009) The transcription repressor, ZEB1, cooperates with CtBP2 and HDAC1 to suppress IL-2 gene activation in T cells. Int Immunol 21(3):227–235PubMedCrossRefGoogle Scholar
  169. 169.
    Migliazza A, Lombardi L, Rocchi M et al (1994) Heterogeneous chromosomal aberrations generate 3’ truncations of the NFKB2/lyt-10 gene in lymphoid malignancies. Blood 84(11):3850–3860PubMedGoogle Scholar
  170. 170.
    Neri A, Fracchiolla NS, Migliazza A, Trecca D, Lombardi L (1996) The involvement of the candidate proto-oncogene NFKB2/lyt-10 in lymphoid malignancies. Leuk Lymphoma 23(1–2):43–48PubMedCrossRefGoogle Scholar
  171. 171.
    Ungewickell A, Bhaduri A, Rios E et al (2015) Genomic analysis of mycosis fungoides and Sezary syndrome identifies recurrent alterations in TNFR2. Nat Genet 47(9):1056–1060PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Ralfkiaer U, Hagedorn PH, Bangsgaard N et al (2011) Diagnostic microRNA profiling in cutaneous T-cell lymphoma (CTCL). Blood 118(22):5891–5900PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Sandoval J, Diaz-Lagares A, Salgado R et al (2015) MicroRNA expression profiling and DNA methylation signature for deregulated microRNA in cutaneous T-cell lymphoma. J Invest Dermatol. 135(4):1128–1137PubMedCrossRefGoogle Scholar
  174. 174.
    Ralfkiaer U, Lindahl LM, Litman T et al (2014) MicroRNA expression in early mycosis fungoides is distinctly different from atopic dermatitis and advanced cutaneous T-cell lymphoma. Anticancer Res 34(12):7207–7217PubMedGoogle Scholar
  175. 175.
    Narducci MG, Arcelli D, Picchio MC et al (2011) MicroRNA profiling reveals that miR-21, miR486 and miR-214 are upregulated and involved in cell survival in Sezary syndrome. Cell Death Dis 2:e151PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Carreon JD, Morton LM, Devesa SS et al (2008) Incidence of lymphoid neoplasms by subtype among six Asian ethnic groups in the United States, 1996-2004. Cancer Causes Control 19(10):1171–1181PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS (2006) Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood 107(1):265–276PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Chan JK, Sin VC, Wong KF et al (1997) Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm. Blood 89(12):4501–4513PubMedPubMedCentralGoogle Scholar
  179. 179.
    Matano S, Nakamura S, Nakamura S et al (1999) Monomorphic agranular natural killer cell lymphoma/leukemia with no Epstein-Barr virus association. Acta Haematol 101(4):206–208PubMedCrossRefPubMedCentralGoogle Scholar
  180. 180.
    Martin AR, Chan WC, Perry DA, Greiner TC, Weisenburger DD (1995) Aggressive natural killer cell lymphoma of the small intestine. Mod Pathol 8(5):467–472PubMedPubMedCentralGoogle Scholar
  181. 181.
    Yagita M, Huang CL, Umehara H et al (2000) A novel natural killer cell line (KHYG-1) from a patient with aggressive natural killer cell leukemia carrying a p53 point mutation. Leukemia 14(5):922–930PubMedCrossRefPubMedCentralGoogle Scholar
  182. 182.
    Chen IM, Whalen M, Bankhurst A et al (2004) A new human natural killer leukemia cell line, IMC-1. A complex chromosomal rearrangement defined by spectral karyotyping: functional and cytogenetic characterization. Leuk Res 28(3):275–284PubMedCrossRefPubMedCentralGoogle Scholar
  183. 183.
    Kulwichit W, Edwards RH, Davenport EM, Baskar JF, Godfrey V, Raab-Traub N (1998) Expression of the Epstein-Barr virus latent membrane protein 1 induces B cell lymphoma in transgenic mice. Proc Natl Acad Sci U S A. 95(20):11963–11968PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Pratt ZL, Kuzembayeva M, Sengupta S, Sugden B (2009) The microRNAs of Epstein-Barr Virus are expressed at dramatically differing levels among cell lines. Virology 386(2):387–397PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    Klinke O, Feederle R, Delecluse HJ (2014) Genetics of Epstein-Barr virus microRNAs. Semin Cancer Biol 26:52–59PubMedCrossRefPubMedCentralGoogle Scholar
  186. 186.
    Vereide DT, Seto E, Chiu YF et al (2014) Epstein-Barr virus maintains lymphomas via its miRNAs. Oncogene 33(10):1258–1264PubMedCrossRefPubMedCentralGoogle Scholar
  187. 187.
    Huang WT, Lin CW (2014) EBV-encoded miR-BART20-5p and miR-BART8 inhibit the IFN-gamma-STAT1 pathway associated with disease progression in nasal NK-cell lymphoma. Am J Pathol 184(4):1185–1197PubMedCrossRefPubMedCentralGoogle Scholar
  188. 188.
    Motsch N, Alles J, Imig J et al (2012) MicroRNA profiling of Epstein-Barr virus-associated NK/T-cell lymphomas by deep sequencing. PLoS ONE 7(8):e42193PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Iqbal J, Kucuk C, Deleeuw RJ et al (2009) Genomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killer-cell malignancies. Leukemia 23(6):1139–1151CrossRefPubMedPubMedCentralGoogle Scholar
  190. 190.
    Huang Y, de Reynies A, de Leval L et al (2010) Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type. Blood 115(6):1226–1237PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Nakashima Y, Tagawa H, Suzuki R et al (2005) Genome-wide array-based comparative genomic hybridization of natural killer cell lymphoma/leukemia: different genomic alteration patterns of aggressive NK-cell leukemia and extranodal Nk/T-cell lymphoma, nasal type. Genes Chromosomes Cancer 44(3):247–255PubMedCrossRefPubMedCentralGoogle Scholar
  192. 192.
    Siu LL, Chan V, Chan JK, Wong KF, Liang R, Kwong YL (2000) Consistent patterns of allelic loss in natural killer cell lymphoma. Am J Pathol 157(6):1803–1809PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Siu LL, Wong KF, Chan JK, Kwong YL (1999) Comparative genomic hybridization analysis of natural killer cell lymphoma/leukemia. Recognition of consistent patterns of genetic alterations. Am J Pathol 155(5):1419–1425PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Ko YH, Choi KE, Han JH, Kim JM, Ree HJ (2001) Comparative genomic hybridization study of nasal-type NK/T-cell lymphoma. Cytometry 46(2):85–91PubMedCrossRefPubMedCentralGoogle Scholar
  195. 195.
    Kucuk C, Iqbal J, Hu X et al (2011) PRDM1 is a tumor suppressor gene in natural killer cell malignancies. Proc Natl Acad Sci USA 108(50):20119–20124PubMedCrossRefPubMedCentralGoogle Scholar
  196. 196.
    Karube K, Nakagawa M, Tsuzuki S et al (2011) Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses. Blood 118(12):3195–3204CrossRefPubMedPubMedCentralGoogle Scholar
  197. 197.
    Kucuk C, Hu X, Iqbal J et al (2013) HACE1 is a tumor suppressor gene candidate in natural killer cell neoplasms. Am J Pathol 182(1):49–55PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Zhang L, Anglesio MS, O’Sullivan M et al (2007) The E3 ligase HACE1 is a critical chromosome 6q21 tumor suppressor involved in multiple cancers. Nat Med 13(9):1060–1069PubMedCrossRefPubMedCentralGoogle Scholar
  199. 199.
    Quintanilla-Martinez L, Kremer M, Keller G et al (2001) p53 Mutations in nasal natural killer/T-cell lymphoma from Mexico: association with large cell morphology and advanced disease. Am J Pathol 159(6):2095–2105PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Frappier L (2012) Contributions of Epstein-Barr nuclear antigen 1 (EBNA1) to cell immortalization and survival. Viruses. 4(9):1537–1547PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Li M, Chen D, Shiloh A et al (2002) Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature 416(6881):648–653PubMedCrossRefPubMedCentralGoogle Scholar
  202. 202.
    Saridakis V, Sheng Y, Sarkari F et al (2005) Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization. Mol Cell 18(1):25–36PubMedCrossRefPubMedCentralGoogle Scholar
  203. 203.
    Oka T, Ouchida M, Koyama M et al (2002) Gene silencing of the tyrosine phosphatase SHP1 gene by aberrant methylation in leukemias/lymphomas. Cancer Res 62(22):6390–6394PubMedPubMedCentralGoogle Scholar
  204. 204.
    Siu LL, Chan JK, Wong KF, Kwong YL (2002) Specific patterns of gene methylation in natural killer cell lymphomas: p73 is consistently involved. Am J Pathol 160(1):59–66PubMedCrossRefPubMedCentralGoogle Scholar
  205. 205.
    Deyoung MP, Ellisen LW (2007) p63 and p73 in human cancer: defining the network. Oncogene 26(36):5169–5183PubMedCrossRefPubMedCentralGoogle Scholar
  206. 206.
    Candi E, Agostini M, Melino G, Bernassola F (2014) How the TP53 family proteins TP63 and TP73 contribute to tumorigenesis: regulators and effectors. Hum Mutat 35(6):702–714PubMedCrossRefPubMedCentralGoogle Scholar
  207. 207.
    Lanier LL (2008) Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol 9(5):495–502PubMedPubMedCentralCrossRefGoogle Scholar
  208. 208.
    Han Y, Amin HM, Frantz C et al (2006) Restoration of shp1 expression by 5-AZA-2’-deoxycytidine is associated with downregulation of JAK3/STAT3 signaling in ALK-positive anaplastic large cell lymphoma. Leukemia 20(9):1602–1609PubMedCrossRefPubMedCentralGoogle Scholar
  209. 209.
    Chim CS, Fung TK, Cheung WC, Liang R, Kwong YL (2004) SOCS1 and SHP1 hypermethylation in multiple myeloma: implications for epigenetic activation of the Jak/STAT pathway. Blood 103(12):4630–4635PubMedCrossRefPubMedCentralGoogle Scholar
  210. 210.
    Chen KF, Su JC, Liu CY et al (2012) A novel obatoclax derivative, SC-2001, induces apoptosis in hepatocellular carcinoma cells through SHP-1-dependent STAT3 inactivation. Cancer Lett 321(1):27–35PubMedCrossRefPubMedCentralGoogle Scholar
  211. 211.
    Kim DJ, Tremblay ML, Digiovanni J (2010) Protein tyrosine phosphatases, TC-PTP, SHP1, and SHP2, cooperate in rapid dephosphorylation of Stat3 in keratinocytes following UVB irradiation. PLoS ONE 5(4):e10290PubMedPubMedCentralCrossRefGoogle Scholar
  212. 212.
    Gupta SC, Phromnoi K, Aggarwal BB (2013) Morin inhibits STAT3 tyrosine 705 phosphorylation in tumor cells through activation of protein tyrosine phosphatase SHP1. Biochem Pharmacol 85(7):898–912PubMedCrossRefPubMedCentralGoogle Scholar
  213. 213.
    Kucuk C, Jiang B, Hu X et al (2015) Activating mutations of STAT5B and STAT3 in lymphomas derived from gammadelta-T or NK cells. Nat Commun. 6:6025PubMedPubMedCentralCrossRefGoogle Scholar
  214. 214.
    Takakuwa T, Dong Z, Nakatsuka S et al (2002) Frequent mutations of Fas gene in nasal NK/T cell lymphoma. Oncogene 21(30):4702–4705PubMedCrossRefPubMedCentralGoogle Scholar
  215. 215.
    Shen L, Liang AC, Lu L et al (2002) Frequent deletion of Fas gene sequences encoding death and transmembrane domains in nasal natural killer/T-cell lymphoma. Am J Pathol 161(6):2123–2131PubMedPubMedCentralCrossRefGoogle Scholar
  216. 216.
    Coppo P, Gouilleux-Gruart V, Huang Y et al (2009) STAT3 transcription factor is constitutively activated and is oncogenic in nasal-type NK/T-cell lymphoma. Leukemia 23(9):1667–1678PubMedPubMedCentralCrossRefGoogle Scholar
  217. 217.
    Yu H, Kortylewski M, Pardoll D (2007) Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 7(1):41–51PubMedCrossRefPubMedCentralGoogle Scholar
  218. 218.
    Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9(11):798–809PubMedPubMedCentralCrossRefGoogle Scholar
  219. 219.
    Wang T, Niu G, Kortylewski M et al (2004) Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 10(1):48–54PubMedCrossRefPubMedCentralGoogle Scholar
  220. 220.
    Koo GC, Tan SY, Tang T et al (2012) Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma. Cancer Discov 2(7):591–597PubMedCrossRefPubMedCentralGoogle Scholar
  221. 221.
    Bouchekioua A, Scourzic L, de Wever O et al (2014) JAK3 deregulation by activating mutations confers invasive growth advantage in extranodal nasal-type natural killer cell lymphoma. Leukemia 28(2):338–348PubMedCrossRefPubMedCentralGoogle Scholar
  222. 222.
    Kimura H, Karube K, Ito Y et al (2014) Rare occurrence of JAK3 mutations in natural killer cell neoplasms in Japan. Leuk Lymphoma 55(4):962–963PubMedCrossRefPubMedCentralGoogle Scholar
  223. 223.
    Jiang L, Gu ZH, Yan ZX, et al. Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma. Nature genetics. 2015:Epub ahead of printGoogle Scholar
  224. 224.
    Dobashi A, Tsuyama N, Asaka R et al (2016) Frequent BCOR aberrations in extranodal NK/T-Cell lymphoma, nasal type. Genes Chromosomes Cancer 55(5):460–471PubMedCrossRefPubMedCentralGoogle Scholar
  225. 225.
    Lee S, Park HY, Kang SY et al (2015) Genetic alterations of JAK/STAT cascade and histone modification in extranodal NK/T-cell lymphoma nasal type. Oncotarget. 6(19):17764–17776PubMedPubMedCentralCrossRefGoogle Scholar
  226. 226.
    Miyazaki K, Yamaguchi M, Imai H et al (2009) Gene expression profiling of peripheral T-cell lymphoma including gammadelta T-cell lymphoma. Blood 113(5):1071–1074CrossRefGoogle Scholar
  227. 227.
    Travert M, Huang Y, de Leval L et al (2012) Molecular features of hepatosplenic T-cell lymphoma unravels potential novel therapeutic targets. Blood 119(24):5795–5806PubMedPubMedCentralCrossRefGoogle Scholar
  228. 228.
    Moffitt AB, Ondrejka SL, McKinney M et al (2017) Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2. J Exp MedGoogle Scholar
  229. 229.
    Davis RE, Brown KD, Siebenlist U, Staudt LM (2001) Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med 194(12):1861–1874PubMedPubMedCentralCrossRefGoogle Scholar
  230. 230.
    Bild AH, Yao G, Chang JT et al (2006) Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature 439(7074):353–357PubMedCrossRefPubMedCentralGoogle Scholar
  231. 231.
    Rosenwald A, Wright G, Leroy K et al (2003) Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med 198(6):851–862PubMedPubMedCentralCrossRefGoogle Scholar
  232. 232.
    Savage KJ, Monti S, Kutok JL et al (2003) The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood 102(12):3871–3879PubMedCrossRefPubMedCentralGoogle Scholar
  233. 233.
    Zinzani PL, Tani M, Musuraca G et al (2006) Phase II study of proteasome inhibitor bortezomib (Velcade®) in patients with relapsed/refractory T-cell lymphoma: preliminary results. Blood 108aGoogle Scholar
  234. 234.
    Piva R, Ruggeri B, Williams M et al (2007) CEP-18770: a novel orally-active proteasome inhibitor with a tumor-selective pharmacological profile competitive with bortezomib. BloodGoogle Scholar
  235. 235.
    Feldman A, Sun D, Law M (2007) Syk Tyrosine Kinase is Overexpressed in the Majority of Peripheral T and NK-cell Lymphomas, and Re. Blood 110:690aGoogle Scholar
  236. 236.
    Wilcox RA, Sun DX, Novak A, Dogan A, Ansell SM, Feldman AL (2010) Inhibition of Syk protein tyrosine kinase induces apoptosis and blocks proliferation in T-cell non-Hodgkin’s lymphoma cell lines. Leukemia 24(1):229–232PubMedCrossRefPubMedCentralGoogle Scholar
  237. 237.
    Piccaluga PP, Rossi M, Agostinelli C et al (2014) Platelet-derived growth factor alpha mediates the proliferation of peripheral T-cell lymphoma cells via an autocrine regulatory pathway. Leukemia 28(8):1687–1697PubMedCrossRefPubMedCentralGoogle Scholar
  238. 238.
    Andrae J, Gallini R, Betsholtz C (2008) Role of platelet-derived growth factors in physiology and medicine. Genes Dev 22(10):1276–1312PubMedPubMedCentralCrossRefGoogle Scholar
  239. 239.
    Perry AM, Molina-Kirsch H, Nathwani BN et al (2011) Classification of non-Hodgkin lymphomas in Guatemala according to the World Health Organization system. Leuk Lymphoma 52(9):1681–1688PubMedCrossRefPubMedCentralGoogle Scholar
  240. 240.
    Wang C, Collins M, Kuchroo VK (2015) Effector T cell differentiation: are master regulators of effector T cells still the masters? Curr Opin Immunol 37:6–10PubMedCrossRefPubMedCentralGoogle Scholar
  241. 241.
    Rudiger T, Weisenburger DD, Anderson JR et al (2002) Peripheral T-cell lymphoma (excluding anaplastic large-cell lymphoma): results from the Non-Hodgkin’s Lymphoma Classification Project. Ann Oncol 13(1):140–149PubMedCrossRefPubMedCentralGoogle Scholar
  242. 242.
    Vose J, Armitage J, Weisenburger D, International TCLP (2008) International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 26(25):4124–4130CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Javeed Iqbal
    • 1
  • Catalina Amador
    • 1
  • Timothy W. McKeithan
    • 2
  • Wing C. Chan
    • 2
    Email author
  1. 1.Pathology and MicrobiologyUniversity of Nebraska Medical CenterOmahaUS
  2. 2.Department of PathologyCity of Hope National Medical CenterDuarteUSA

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