Skip to main content

Advertisement

SpringerLink
Log in

Mature T-cell and NK-cell lymphomas: updates on molecular genetic features

  • Progress in Hematology
  • T-cell lymphoma
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Mature T-cell and NK-cell lymphomas are a heterogeneous group of rare and typically aggressive neoplasms. Diagnosis and subclassification have historically relied primarily on the integration of clinical, histologic, and immunophenotypic features, which often overlap. The widespread application of a variety of genomic techniques in recent years has provided extensive insight into the pathobiology of these diseases, allowing for more precise diagnostic classification, improved prognostication, and development of novel therapies. In this review, we summarize the genomic features of the most common types of mature T-cell and NK-cell lymphomas with a particular focus on the contribution of genomics to biologic insight, classification, risk stratification, and select therapies in the context of the recently published International Consensus and updated World Health Organization classification systems.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia. 2022;36(7):1720–48.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Campo E, Jaffe ES, Cook JR, et al. The international consensus classification of mature lymphoid neoplasms: a report from the clinical advisory committee. Blood. 2022;140(11):1229–53.

    Article  CAS  PubMed  Google Scholar 

  3. de Leval L, Parrens M, Le Bras F, et al. Angioimmunoblastic T-cell lymphoma is the most common T-cell lymphoma in two distinct French information data sets. Haematologica. 2015;100(9):e361-364.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Parrilla Castellar ER, Jaffe ES, Said JW, et al. ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. Blood. 2014;124(9):1473–80.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Savage KJ, Harris NL, Vose 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.

    Article  CAS  PubMed  Google Scholar 

  6. Morris SW, Kirstein MN, Valentine MB, 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.

    Article  CAS  PubMed  Google Scholar 

  7. Pulford K, Lamant L, Espinos E, et al. The emerging normal and disease-related roles of anaplastic lymphoma kinase. Cell Mol Life Sci. 2004;61(23):2939–53.

    Article  CAS  PubMed  Google Scholar 

  8. Pulford K, Lamant L, Morris SW, et al. Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1. Blood. 1997;89(4):1394–404.

    Article  CAS  PubMed  Google Scholar 

  9. Bai RY, Dieter P, Peschel C, Morris SW, Duyster J. Nucleophosmin-anaplastic lymphoma kinase of large-cell anaplastic lymphoma is a constitutively active tyrosine kinase that utilizes phospholipase C-gamma to mediate its mitogenicity. Mol Cell Biol. 1998;18(12):6951–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bai RY, Ouyang T, Miething C, Morris SW, Peschel C, Duyster J. Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway. Blood. 2000;96(13):4319–27.

    Article  CAS  PubMed  Google Scholar 

  11. Fujimoto J, Shiota M, Iwahara T, et al. Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5). Proc Natl Acad Sci U S A. 1996;93(9):4181–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zamo A, Chiarle R, Piva R, et al. Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death. Oncogene. 2002;21(7):1038–47.

    Article  CAS  PubMed  Google Scholar 

  13. Marzec M, Zhang Q, Goradia A, et al. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7–H1). Proc Natl Acad Sci U S A. 2008;105(52):20852–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chiarle R, Simmons WJ, Cai H, et al. Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target. Nat Med. 2005;11(6):623–9.

    Article  CAS  PubMed  Google Scholar 

  15. Bossi E, Aroldi A, Brioschi FA, et al. Phase two study of crizotinib in patients with anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma relapsed/refractory to chemotherapy. Am J Hematol. 2020;95(12):E319-e321.

    Article  CAS  PubMed  Google Scholar 

  16. Boi M, Rinaldi A, Kwee I, et al. PRDM1/BLIMP1 is commonly inactivated in anaplastic large T-cell lymphoma. Blood. 2013;122(15):2683–93.

    Article  CAS  PubMed  Google Scholar 

  17. Lobello C, Tichy B, Bystry V, et al. STAT3 and TP53 mutations associate with poor prognosis in anaplastic large cell lymphoma. Leukemia. 2021;35(5):1500–5.

    Article  CAS  PubMed  Google Scholar 

  18. Zettl A, Rüdiger T, Konrad MA, et al. Genomic profiling of peripheral T-cell lymphoma, unspecified, and anaplastic large T-cell lymphoma delineates novel recurrent chromosomal alterations. Am J Pathol. 2004;164(5):1837–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Salaverria I, Beà S, Lopez-Guillermo A, et al. Genomic profiling reveals different genetic aberrations in systemic ALK-positive and ALK-negative anaplastic large cell lymphomas. Br J Haematol. 2008;140(5):516–26.

    Article  PubMed  Google Scholar 

  20. Piva R, Agnelli L, Pellegrino E, et al. Gene expression profiling uncovers molecular classifiers for the recognition of anaplastic large-cell lymphoma within peripheral T-cell neoplasms. J Clin Oncol. 2010;28(9):1583–90.

    Article  CAS  PubMed  Google Scholar 

  21. Iqbal J, Wright G, Wang C, et al. Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma. Blood. 2014;123(19):2915–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Luchtel RA, Dasari S, Oishi N, et al. Molecular profiling reveals immunogenic cues in anaplastic large cell lymphomas with DUSP22 rearrangements. Blood. 2018;132(13):1386–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Iqbal J, Weisenburger DD, Greiner TC, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Liu C, Iqbal J, Teruya-Feldstein J, et al. MicroRNA expression profiling identifies molecular signatures associated with anaplastic large cell lymphoma. Blood. 2013;122(12):2083–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Merkel O, Hamacher F, Laimer D, et al. 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. 2010;107(37):16228–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Larose H, Prokoph N, Matthews JD, et al. Whole exome sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target. Haematologica. 2021;106(6):1693–704.

    Article  CAS  PubMed  Google Scholar 

  27. Feldman AL, Dogan A, Smith DI, et al. Discovery of recurrent t(6;7)(p.253;q.323) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing. Blood. 2011;117(3):915–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Vasmatzis G, Johnson SH, Knudson RA, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hapgood G, Ben-Neriah S, Mottok A, et al. Identification of high-risk DUSP22-rearranged ALK-negative anaplastic large cell lymphoma. Br J Haematol. 2019;186(3):e28–31.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Onaindia A, de Villambrosía SG, Prieto-Torres L, et al. DUSP22-rearranged anaplastic lymphomas are characterized by specific morphological features and a lack of cytotoxic and JAK/STAT surrogate markers. Haematologica. 2019;104(4):e158–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pedersen MB, Hamilton-Dutoit SJ, Bendix K, et al. DUSP22 and TP63 rearrangements predict outcome of ALK-negative anaplastic large cell lymphoma: a Danish cohort study. Blood. 2017;130(4):554–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wada DA, Law ME, Hsi ED, et al. Specificity of IRF4 translocations for primary cutaneous anaplastic large cell lymphoma: a multicenter study of 204 skin biopsies. Mod Pathol. 2011;24(4):596–605.

    Article  CAS  PubMed  Google Scholar 

  33. Karai LJ, Kadin ME, Hsi ED, et al. Chromosomal rearrangements of 6p253 define a new subtype of lymphomatoid papulosis. Am J Surg Pathol. 2013;37(8):1173–81.

    Article  PubMed  Google Scholar 

  34. King RL, Dao LN, McPhail ED, et al. Morphologic Features of ALK-negative Anaplastic Large Cell Lymphomas With DUSP22 Rearrangements. Am J Surg Pathol. 2016;40(1):36–43.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Luchtel RA, Zimmermann MT, Hu G, et al. Recurrent MSC (E116K) mutations in ALK-negative anaplastic large cell lymphoma. Blood. 2019;133(26):2776–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pedersen MB, Relander T, Lauritzsen GF, et al. The impact of upfront autologous transplant on the survival of adult patients with ALCL and PTCL-NOS according to their ALK, DUSP22 and TP63 gene rearrangement status - a joined nordic lymphoma group and mayo clinic analysis. Blood. 2017;130(Supplement 1):822–822.

    Article  Google Scholar 

  37. Horwitz SM, Ansell S, Ai WZ, et al. T-Cell Lymphomas, version 22022, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2022;20(3):285–308.

    Article  CAS  PubMed  Google Scholar 

  38. Scott DW, Mungall KL, Ben-Neriah S, et al. TBL1XR1/TP63: a novel recurrent gene fusion in B-cell non-Hodgkin lymphoma. Blood. 2012;119(21):4949–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Klairmont MM, Ward N. Co-occurring rearrangements of DUSP22 and TP63 define a rare genetic subset of ALK-negative anaplastic large cell lymphoma with inferior survival outcomes. Leuk Lymphoma. 2022;63(2):506–8.

    Article  CAS  PubMed  Google Scholar 

  40. Crescenzo R, Abate F, Lasorsa E, et al. Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell. 2015;27(4):516–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Fitzpatrick MJ, Massoth LR, Marcus C, et al. JAK2 rearrangements are a recurrent alteration in CD30+ Systemic T-Cell Lymphomas With anaplastic morphology. Am J Surg Pathol. 2021;45(7):895–904.

    PubMed  Google Scholar 

  42. Hu G, Dasari S, Asmann YW, et al. Targetable fusions of the FRK tyrosine kinase in ALK-negative anaplastic large cell lymphoma. Leukemia. 2018;32(2):565–9.

    Article  CAS  PubMed  Google Scholar 

  43. Velusamy T, Kiel MJ, Sahasrabuddhe AA, et al. A novel recurrent NPM1-TYK2 gene fusion in cutaneous CD30-positive lymphoproliferative disorders. Blood. 2014;124(25):3768–71.

    Article  CAS  PubMed  Google Scholar 

  44. Boddicker RL, Razidlo GL, Dasari S, et al. Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma. Blood. 2016;128(9):1234–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Scarfò I, Pellegrino E, Mereu E, et al. Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts. Blood. 2016;127(2):221–32.

    Article  PubMed  Google Scholar 

  46. Liang HC, Costanza M, Prutsch N, et al. Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma. Nat Commun. 2021;12(1):5577.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Agnelli L, Mereu E, Pellegrino E, et al. Identification of a 3-gene model as a powerful diagnostic tool for the recognition of ALK-negative anaplastic large-cell lymphoma. Blood. 2012;120(6):1274–81.

    Article  CAS  PubMed  Google Scholar 

  48. Clemens MW, Medeiros LJ, Butler CE, et al. Complete surgical excision is essential for the management of patients with breast implant-associated anaplastic large-cell lymphoma. J Clin Oncol. 2016;34(2):160–8.

    Article  CAS  PubMed  Google Scholar 

  49. Ferrufino-Schmidt MC, Medeiros LJ, Liu H, et al. Clinicopathologic features and prognostic impact of lymph node involvement in patients with breast implant-associated anaplastic large cell lymphoma. Am J Surg Pathol. 2018;42(3):293–305.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Laurent C, Delas A, Gaulard P, et al. Breast implant-associated anaplastic large cell lymphoma: two distinct clinicopathological variants with different outcomes. Ann Oncol. 2016;27(2):306–14.

    Article  CAS  PubMed  Google Scholar 

  51. Quesada AE, Medeiros LJ, Clemens MW, Ferrufino-Schmidt MC, Pina-Oviedo S, Miranda RN. Breast implant-associated anaplastic large cell lymphoma: a review. Mod Pathol. 2019;32(2):166–88.

    Article  PubMed  Google Scholar 

  52. Laurent C, Nicolae A, Laurent C, et al. Gene alterations in epigenetic modifiers and JAK-STAT signaling are frequent in breast implant-associated ALCL. Blood. 2020;135(5):360–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Lechner MG, Megiel C, Church CH, et al. Survival signals and targets for therapy in breast implant-associated ALK–anaplastic large cell lymphoma. Clinical Cancer Res. 2012;18(17):4549–59.

    Article  CAS  Google Scholar 

  54. Los-de Vries GT, de Boer M, van Dijk E, et al. Chromosome 20 loss is characteristic of breast implant-associated anaplastic large cell lymphoma. Blood. 2020;136(25):2927–32.

    Article  CAS  PubMed  Google Scholar 

  55. Quesada AE, Zhang Y, Ptashkin R, et al. Next generation sequencing of breast implant-associated anaplastic large cell lymphomas reveals a novel STAT3-JAK2 fusion among other activating genetic alterations within the JAK-STAT pathway. Breast J. 2021;27(4):314–21.

    Article  CAS  PubMed  Google Scholar 

  56. Gerbe A, Alame M, Dereure O, et al. Systemic, primary cutaneous, and breast implant-associated ALK-negative anaplastic large-cell lymphomas present similar biologic features despite distinct clinical behavior. Virchows Arch. 2019;475(2):163–74.

    Article  CAS  PubMed  Google Scholar 

  57. Tabanelli V, Corsini C, Fiori S, et al. Recurrent PDL1 expression and PDL1 (CD274) copy number alterations in breast implant-associated anaplastic large cell lymphomas. Hum Pathol. 2019;90:60–9.

    Article  CAS  PubMed  Google Scholar 

  58. Blombery P, Thompson E, Ryland GL, et al. Frequent activating STAT3 mutations and novel recurrent genomic abnormalities detected in breast implant-associated anaplastic large cell lymphoma. Oncotarget. 2018;9(90):36126–36.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Di Napoli A, De Cecco L, Piccaluga PP, et al. Transcriptional analysis distinguishes breast implant-associated anaplastic large cell lymphoma from other peripheral T-cell lymphomas. Mod Pathol. 2019;32(2):216–30.

    Article  PubMed  Google Scholar 

  60. Oishi N, Hundal T, Phillips JL, et al. Molecular profiling reveals a hypoxia signature in breast implant-associated anaplastic large cell lymphoma. Haematologica. 2021;106(6):1714–24.

    Article  CAS  PubMed  Google Scholar 

  61. Oishi N, Brody GS, Ketterling RP, et al. Genetic subtyping of breast implant-associated anaplastic large cell lymphoma. Blood. 2018;132(5):544–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Di Napoli A, Jain P, Duranti E, et al. Targeted next generation sequencing of breast implant-associated anaplastic large cell lymphoma reveals mutations in JAK/STAT signalling pathway genes, TP53 and DNMT3A. Br J Haematol. 2018;180(5):741–4.

    Article  PubMed  Google Scholar 

  63. Adlard J, Burton C, Turton P. Increasing evidence for the association of breast implant-associated anaplastic large cell lymphoma and li fraumeni syndrome. Case Rep Genet. 2019;2019:5647940.

    PubMed  PubMed Central  Google Scholar 

  64. Blombery P, Thompson ER, Jones K, et al. Whole exome sequencing reveals activating JAK1 and STAT3 mutations in breast implant-associated anaplastic large cell lymphoma anaplastic large cell lymphoma. Haematologica. 2016;101(9):e387-390.

    Article  PubMed  PubMed Central  Google Scholar 

  65. de Boer M, Hauptmann M, Hijmering NJ, et al. Increased prevalence of BRCA1/2 mutations in women with macrotextured breast implants and anaplastic large cell lymphoma of the breast. Blood. 2020;136(11):1368–72.

    Article  PubMed  Google Scholar 

  66. de Leval L, Rickman DS, Thielen C, 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.

    Article  PubMed  Google Scholar 

  67. Piccaluga PP, Agostinelli C, Califano A, et al. Gene expression analysis of angioimmunoblastic lymphoma indicates derivation from T follicular helper cells and vascular endothelial growth factor deregulation. Can Res. 2007;67(22):10703–10.

    Article  CAS  Google Scholar 

  68. Cortés JR, Palomero T. The curious origins of angioimmunoblastic T-cell lymphoma. Curr Opin Hematol. 2016;23(4):434–43.

    Article  PubMed  Google Scholar 

  69. Crotty S. T follicular helper cell biology: a decade of discovery and diseases. Immunity. 2019;50(5):1132–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Heavican TB, Bouska A, Yu J, et al. Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma. Blood. 2019;133(15):1664–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Odejide O, Weigert O, Lane AA, et al. A targeted mutational landscape of angioimmunoblastic T-cell lymphoma. Blood. 2014;123(9):1293–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Palomero T, Couronné 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Sakata-Yanagimoto M, Enami T, Yoshida K, et al. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat Genet. 2014;46(2):171–5.

    Article  CAS  PubMed  Google Scholar 

  74. Steinhilber J, Mederake M, Bonzheim I, et al. The pathological features of angioimmunoblastic T-cell lymphomas with IDH2(R172) mutations. Mod Pathol. 2019;32(8):1123–34.

    Article  CAS  PubMed  Google Scholar 

  75. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Yao WQ, Wu F, Zhang W, et al. Angioimmunoblastic T-cell lymphoma contains multiple clonal T-cell populations derived from a common TET2 mutant progenitor cell. J Pathol. 2020;250(3):346–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 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(12): e264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Dobay MP, Lemonnier F, Missiaglia E, et al. Integrative clinicopathological and molecular analyses of angioimmunoblastic T-cell lymphoma and other nodal lymphomas of follicular helper T-cell origin. Haematologica. 2017;102(4):e148–51.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Scourzic L, Couronné L, Pedersen MT, et al. DNMT3A(R882H) mutant and Tet2 inactivation cooperate in the deregulation of DNA methylation control to induce lymphoid malignancies in mice. Leukemia. 2016;30(6):1388–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Yoo HY, Sung MK, Lee SH, et al. A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma. Nat Genet. 2014;46(4):371–5.

    Article  CAS  PubMed  Google Scholar 

  81. Yoo HY, Kim P, Kim WS, et al. Frequent CTLA4-CD28 gene fusion in diverse types of T-cell lymphoma. Haematologica. 2016;101(6):757–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Cortes JR, Ambesi-Impiombato A, Couronné L, et al. RHOA G17V induces T follicular helper cell specification and promotes Lymphomagenesis. Cancer Cell. 2018;33(2):259-273.e257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ng SY, Brown L, Stevenson K, et al. RhoA G17V is sufficient to induce autoimmunity and promotes T-cell lymphomagenesis in mice. Blood. 2018;132(9):935–47.

    Article  CAS  PubMed  Google Scholar 

  84. Fujisawa M, Sakata-Yanagimoto M, Nishizawa S, et al. Activation of RHOA-VAV1 signaling in angioimmunoblastic T-cell lymphoma. Leukemia. 2018;32(3):694–702.

    Article  CAS  PubMed  Google Scholar 

  85. Chiba S, Sakata-Yanagimoto M. Advances in understanding of angioimmunoblastic T-cell lymphoma. Leukemia. 2020;34(10):2592–606.

    Article  PubMed  PubMed Central  Google Scholar 

  86. DiToro D, Winstead CJ, Pham D, et al. Differential IL-2 expression defines developmental fates of follicular versus nonfollicular helper T cells. Science. 2018. https://doi.org/10.1126/science.aao2933.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Nagao R, Kikuti YY, Carreras J, et al. Clinicopathologic analysis of angioimmunoblastic T-cell Lymphoma with or without RHOA G17V mutation using formalin-fixed paraffin-embedded sections. Am J Surg Pathol. 2016;40(8):1041–50.

    Article  PubMed  Google Scholar 

  88. Ondrejka SL, Grzywacz B, Bodo J, et al. Angioimmunoblastic T-cell Lymphomas with the RHOA p.Gly17Val mutation have classic clinical and pathologic features. Am J Surg Pathol. 2016;40(3):335–41.

    Article  PubMed  Google Scholar 

  89. Cairns RA, Iqbal J, Lemonnier F, et al. IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. Blood. 2012;119(8):1901–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Yang H, Ye D, Guan KL, Xiong Y. IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin CANCER Res. 2012;18(20):5562–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. 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.

    Article  CAS  PubMed  Google Scholar 

  92. Drieux F, Ruminy P, Sater V, et al. Detection of gene fusion transcripts in peripheral T-Cell lymphoma using a multiplexed targeted sequencing assay. J Mole Diagnost. 2021;23(8):929–40.

    Article  CAS  Google Scholar 

  93. Jaiswal S, Ebert BL. Clonal hematopoiesis in human aging and disease. Science. 2019. https://doi.org/10.1126/science.aan4673.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Reddy A, Zhang J, Davis NS, et al. Genetic and functional drivers of diffuse Large B Cell Lymphoma. Cell. 2017;171(2):481-494.e415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Couronné L, Bastard C, Bernard OA. TET2 and DNMT3A mutations in human T-cell lymphoma. N Engl J Med. 2012;366(1):95–6.

    Article  PubMed  Google Scholar 

  96. Lemonnier F, Cairns RA, Inoue S, et al. The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development. Proc Natl Acad Sci U S A. 2016;113(52):15084–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Nguyen TB, Sakata-Yanagimoto M, Asabe Y, et al. Identification of cell-type-specific mutations in nodal T-cell lymphomas. Blood Cancer J. 2017;7(1): e516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Quivoron C, Couronné L, Della Valle V, et al. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell. 2011;20(1):25–38.

    Article  CAS  PubMed  Google Scholar 

  99. Cheng S, Zhang W, Inghirami G, Tam W. Mutation analysis links angioimmunoblastic T-cell lymphoma to clonal hematopoiesis and smoking. Elife. 2021. https://doi.org/10.7554/eLife.66395.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Lewis NE, Petrova-Drus K, Huet S, et al. Clonal hematopoiesis in angioimmunoblastic T-cell lymphoma with divergent evolution to myeloid neoplasms. Blood Adv. 2020;4(10):2261–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Fujisawa M, Nguyen TB, Abe Y, et al. Clonal germinal center B cells function as a niche for T-cell lymphoma. Blood. 2022;140(18):1937–50.

    Article  CAS  PubMed  Google Scholar 

  102. Attygalle AD, Dobson R, Chak PK, et al. Parallel evolution of two distinct lymphoid proliferations in clonal haematopoiesis. Histopathology. 2022;80(5):847–58.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Huang Y, Moreau A, Dupuis J, et al. Peripheral T-cell lymphomas with a follicular growth pattern are derived from follicular helper T cells (TFH) and may show overlapping features with angioimmunoblastic T-cell lymphomas. Am J Surg Pathol. 2009;33(5):682–90.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Debackere K, van der Krogt JA, Tousseyn T, et al. FER and FES tyrosine kinase fusions in follicular T-cell lymphoma. Blood. 2020;135(8):584–8.

    Article  PubMed  Google Scholar 

  105. Streubel B, Vinatzer U, Willheim M, Raderer M, Chott A. Novel t(5;9)(q33;q22) fuses ITK to SYK in unspecified peripheral T-cell lymphoma. Leukemia. 2006;20(2):313–8.

    Article  CAS  PubMed  Google Scholar 

  106. Attygalle AD, Feldman AL, Dogan A. ITK/SYK translocation in angioimmunoblastic T-cell lymphoma. Am J Surg Pathol. 2013;37(9):1456–7.

    Article  PubMed  Google Scholar 

  107. Falchi L, Ma H, Klein S, et al. Combined oral 5-azacytidine and romidepsin are highly effective in patients with PTCL: a multicenter phase 2 study. Blood. 2021;137(16):2161–70.

    Article  CAS  PubMed  Google Scholar 

  108. Ghione P, Faruque P, Mehta-Shah N, et al. T follicular helper phenotype predicts response to histone deacetylase inhibitors in relapsed/refractory peripheral T-cell lymphoma. Blood Adv. 2020;4(19):4640–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Vose J, Armitage J, Weisenburger D. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008;26(25):4124–30.

    Article  PubMed  Google Scholar 

  110. Amador C, Greiner TC, Heavican TB, et al. Reproducing the molecular subclassification of peripheral T-cell lymphoma-NOS by immunohistochemistry. Blood. 2019;134(24):2159–70.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Nicolae A, Bouilly J, Lara D, et al. Nodal cytotoxic peripheral T-cell lymphoma occurs frequently in the clinical setting of immunodysregulation and is associated with recurrent epigenetic alterations. Mod Pathol. 2022;35(8):1126–36.

    Article  CAS  PubMed  Google Scholar 

  112. Maura F, Dodero A, Carniti C, et al. <i>CDKN2A</i> deletion is a frequent event associated with poor outcome in patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS). Haematologica. 2021;106(11):2918–26.

    Article  CAS  PubMed  Google Scholar 

  113. Watatani Y, Sato Y, Miyoshi H, et al. Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling. Leukemia. 2019;33(12):2867–83.

    Article  CAS  PubMed  Google Scholar 

  114. Laginestra MA, Cascione L, Motta G, et al. Whole exome sequencing reveals mutations in FAT1 tumor suppressor gene clinically impacting on peripheral T-cell lymphoma not otherwise specified. Mod Pathol. 2020;33(2):179–87.

    Article  CAS  PubMed  Google Scholar 

  115. Abate F, da Silva-Almeida AC, Zairis S, et al. Activating mutations and translocations in the guanine exchange factor VAV1 in peripheral T-cell lymphomas. Proc Natl Acad Sci U S A. 2017;114(4):764–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Debackere K, Marcelis L, Demeyer S, et al. Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified. Nat Commun. 2021;12(1):3705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Kato S, Yamashita D, Nakamura S. Nodal EBV+ cytotoxic T-cell lymphoma: A literature review based on the 2017 WHO classification. J Clin Exp Hematop. 2020;60(2):30–6.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Ng SB, Chung TH, Kato S, et al. Epstein-Barr virus-associated primary nodal T/NK-cell lymphoma shows a distinct molecular signature and copy number changes. Haematologica. 2018;103(2):278–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Wai CMM, Chen S, Phyu T, et al. Immune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS. Haematologica. 2022;107(8):1864–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Laurini JA, Perry AM, Boilesen E, et al. Classification of non-Hodgkin lymphoma in Central and South America: a review of 1028 cases. Blood. 2012;120(24):4795–801.

    Article  CAS  PubMed  Google Scholar 

  121. Hong M, Lee T, Young Kang S, Kim SJ, Kim W, Ko YH. Nasal-type NK/T-cell lymphomas are more frequently T rather than NK lineage based on T-cell receptor gene, RNA, and protein studies: lineage does not predict clinical behavior. Mod Pathol. 2016;29(5):430–43.

    Article  CAS  PubMed  Google Scholar 

  122. Dong G, Liu X, Wang L, et al. Genomic profiling identifies distinct genetic subtypes in extra-nodal natural killer/T-cell lymphoma. Leukemia. 2022;36(8):2064–75.

    Article  CAS  PubMed  Google Scholar 

  123. Huang Y, de Reyniès A, de Leval L, et al. Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type. Blood. 2010;115(6):1226–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 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.

    Article  CAS  PubMed  Google Scholar 

  125. Nakashima Y, Tagawa H, Suzuki R, et al. 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. 2005;44(3):247–55.

    Article  CAS  PubMed  Google Scholar 

  126. Chen YW, Guo T, Shen L, et al. Receptor-type tyrosine-protein phosphatase κ directly targets STAT3 activation for tumor suppression in nasal NK/T-cell lymphoma. Blood. 2015;125(10):1589–600.

    Article  CAS  PubMed  Google Scholar 

  127. Karube K, Nakagawa M, Tsuzuki S, et al. Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses. Blood. 2011;118(12):3195–204.

    Article  CAS  PubMed  Google Scholar 

  128. Ng SB, Selvarajan V, Huang G, et al. Activated oncogenic pathways and therapeutic targets in extranodal nasal-type NK/T cell lymphoma revealed by gene expression profiling. J Pathol. 2011;223(4):496–510.

    Article  CAS  PubMed  Google Scholar 

  129. Kim H, Ko YH. The pathologic and genetic characteristics of extranodal NK/T-Cell Lymphoma. Life. 2022. https://doi.org/10.3390/life12010073.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Montes-Mojarro IA, Chen BJ, Ramirez-Ibarguen AF, et al. Mutational profile and EBV strains of extranodal NK/T-cell lymphoma, nasal type in Latin America. Mod Pathol. 2020;33(5):781–91.

    Article  CAS  PubMed  Google Scholar 

  131. 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.

    Article  CAS  PubMed  Google Scholar 

  132. Küçük C, Hu X, Jiang B, 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.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Bi XW, Wang H, Zhang WW, et al. PD-L1 is upregulated by EBV-driven LMP1 through NF-κB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma. J Hematol Oncol. 2016;9(1):109.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Kataoka K, Miyoshi H, Sakata S, et al. Frequent structural variations involving programmed death ligands in Epstein-Barr virus-associated lymphomas. Leukemia. 2019;33(7):1687–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Lim JQ, Huang D, Tang T, et al. Whole-genome sequencing identifies responders to Pembrolizumab in relapse/refractory natural-killer/T cell lymphoma. Leukemia. 2020;34(12):3413–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Song TL, Nairismägi ML, Laurensia Y, et al. Oncogenic activation of the STAT3 pathway drives PD-L1 expression in natural killer/T-cell lymphoma. Blood. 2018;132(11):1146–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Kim SJ, Lim JQ, Laurensia Y, et al. Avelumab for the treatment of relapsed or refractory extranodal NK/T-cell lymphoma: an open-label phase 2 study. Blood. 2020;136(24):2754–63.

    Article  CAS  PubMed  Google Scholar 

  138. Xiong J, Cui BW, Wang N, et al. Genomic and Transcriptomic characterization of natural killer T Cell Lymphoma. Cancer Cell. 2020;37(3):403-419.e406.

    Article  CAS  PubMed  Google Scholar 

  139. Cho J, Kim SJ, Park WY, et al. Immune subtyping of extranodal NK/T-cell lymphoma: a new biomarker and an immune shift during disease progression. Mod Pathol. 2020;33(4):603–15.

    Article  CAS  PubMed  Google Scholar 

  140. Li Z, Xia Y, Feng LN, et al. Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study. Lancet Oncol. 2016;17(9):1240–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Lin GW, Xu C, Chen K, et al. Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study in multiple populations. Lancet Oncol. 2020;21(2):306–16.

    Article  CAS  PubMed  Google Scholar 

  142. Tian XP, Ma SY, Young KH, et al. A composite single-nucleotide polymorphism prediction signature for extranodal natural killer/T-cell lymphoma. Blood. 2021;138(6):452–63.

    Article  CAS  PubMed  Google Scholar 

  143. Suzumiya J, Ohshima K, Takeshita M, et al. Nasal lymphomas in Japan: a high prevalence of Epstein-Barr virus type A and deletion within the latent membrane protein gene. Leuk Lymphoma. 1999;35(5–6):567–78.

    Article  CAS  PubMed  Google Scholar 

  144. Peng RJ, Han BW, Cai QQ, et al. Genomic and transcriptomic landscapes of Epstein-Barr virus in extranodal natural killer T-cell lymphoma. Leukemia. 2019;33(6):1451–62.

    Article  PubMed  Google Scholar 

  145. de Mel S, Hue SS, Jeyasekharan AD, Chng WJ, Ng SB. Molecular pathogenic pathways in extranodal NK/T cell lymphoma. J Hematol Oncol. 2019;12(1):33.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Li L, Ma BBY, Chan ATC, Chan FKL, Murray P, Tao Q. Epstein-Barr Virus-Induced Epigenetic pathogenesis of viral-associated lymphoepithelioma-like carcinomas and natural killer/T-Cell lymphomas. Pathogens. 2018. https://doi.org/10.3390/pathogens7030063.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Tsukasaki K, Hermine O, Bazarbachi A, et al. Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma: a proposal from an international consensus meeting. J Clinical oncology. 2009;27(3):453–9.

    Article  Google Scholar 

  148. Bangham CRM, Matsuoka M. Human T-cell leukaemia virus type 1: parasitism and pathogenesis. Philos Trans R Soc Lond B Biol Sci. 2017;372:1732.

    Article  Google Scholar 

  149. Kataoka K, Nagata Y, Kitanaka A, et al. Integrated molecular analysis of adult T cell leukemia/lymphoma. Nat Genet. 2015;47(11):1304–15.

    Article  CAS  PubMed  Google Scholar 

  150. Marçais A, Lhermitte L, Artesi M, et al. Targeted deep sequencing reveals clonal and subclonal mutational signatures in adult T-cell leukemia/lymphoma and defines an unfavorable indolent subtype. Leukemia. 2021;35(3):764–76.

    Article  PubMed  Google Scholar 

  151. Shah UA, Chung EY, Giricz O, et al. North American ATLL has a distinct mutational and transcriptional profile and responds to epigenetic therapies. Blood. 2018;132(14):1507–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Kogure Y, Kameda T, Koya J, et al. Whole-genome landscape of adult T-cell leukemia/lymphoma. Blood. 2022;139(7):967–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Nakagawa M, Schmitz R, Xiao W, et al. Gain-of-function CCR4 mutations in adult T cell leukemia/lymphoma. J Exp Med. 2014;211(13):2497–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Sakamoto Y, Ishida T, Masaki A, et al. CCR4 mutations associated with superior outcome of adult T-cell leukemia/lymphoma under mogamulizumab treatment. Blood. 2018;132(7):758–61.

    Article  PubMed  Google Scholar 

  155. Tanaka N, Mori S, Kiyotani K, et al. Genomic determinants impacting the clinical outcome of mogamulizumab treatment for adult T-cell leukemia/lymphoma. Haematologica. 2022;107(10):2418–31.

    Article  PubMed  PubMed Central  Google Scholar 

  156. Kataoka K, Shiraishi Y, Takeda Y, et al. Aberrant PD-L1 expression through 3’-UTR disruption in multiple cancers. Nature. 2016;534(7607):402–6.

    Article  CAS  PubMed  Google Scholar 

  157. Kataoka K, Iwanaga M, Yasunaga JI, et al. Prognostic relevance of integrated genetic profiling in adult T-cell leukemia/lymphoma. Blood. 2018;131(2):215–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Sakamoto Y, Ishida T, Masaki A, et al. Clinical significance of TP53 mutations in adult T-cell leukemia/lymphoma. Br J Haematol. 2021;195(4):571–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Hematopathology Service, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Natasha E. Lewis, Rohan Sardana & Ahmet Dogan

Authors
  1. Natasha E. Lewis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rohan Sardana
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ahmet Dogan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Natasha E. Lewis.

Ethics declarations

Conflict of interest

N.E.L. consults and is on an advisory board for United States Drug Testing Laboratories. A.D. has received personal consultancy fees from Roche, Incyte, Loxo Oncology and EUSA Pharma and research support from Roche and Takeda. The remaining author declares no competing financial interests related to this work.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lewis, N.E., Sardana, R. & Dogan, A. Mature T-cell and NK-cell lymphomas: updates on molecular genetic features. Int J Hematol 117, 475–491 (2023). https://doi.org/10.1007/s12185-023-03537-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-023-03537-7

Keywords

Search

Navigation