Skip to main content
SpringerLink
Log in

Pathogenesis of T-Non-Hodgkin’s Lymphoma

  • Chapter
  • First Online:
Non-Hodgkin's Lymphoma in Childhood and Adolescence

  • 748 Accesses

Abstract

T-lymphoblastic lymphoma (T-LBL) is by far the most common T-NHL in children and adolescents, typically presenting with a mediastinal mass and advanced disease. The molecular pathology of T-LBL is similar to T-acute lymphoblastic leukemia (T-ALL), with frequent activating mutations of the NOTCH1 pathway and signaling kinase molecules, and translocations of the T-receptor gene (TR) loci. There are several recognized differences with the T-ALL genotype, for example, differing patterns of loss of heterozygosity on chromosome 6q (6qLOH) that have been reported to predict prognosis. As in T-ALL, T-LBL can been categorized according to TR rearrangement status and transcriptional profiling. Current treatment efforts are based on therapy stratification according to disease risk, which is principally defined by genotype (i.e., NOTCH1/FBXW7 mutational status).

Other T-NHLs in this age group are classified among a heterogeneous group of peripheral T-cell lymphomas (PTCL). Categorization of these rare diseases continues to evolve, in concert with advancements in knowledge of their diverse molecular pathology.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. You MJ, Medeiros LJ, Hsi ED. T-lymphoblastic leukemia/lymphoma. Am J Clin Pathol. 2015;144(3):411–22.

    Article  CAS  Google Scholar 

  2. Smock KJ, Nelson M, Tripp SR, Sanger WG, Abromowitch M, Cairo MS, et al. Characterization of childhood precursor T-lymphoblastic lymphoma by immunophenotyping and fluorescent in situ hybridization: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2008;51(4):489–94.

    Article  Google Scholar 

  3. Burkhardt B, Mueller S, Khanam T, Perkins SL. Current status and future directions of T-lymphoblastic lymphoma in children and adolescents. Br J Haematol. 2016;173(4):545–59.

    Article  Google Scholar 

  4. Swerdlow SH. Cancer IAfRo, organization WH. International Agency for Research on Cancer: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues; 2008.

    Google Scholar 

  5. Burkhardt B. Paediatric lymphoblastic T-cell leukaemia and lymphoma: one or two diseases? Br J Haematol. 2010;149(5):653–68.

    Article  CAS  Google Scholar 

  6. Uyttebroeck A, Vanhentenrijk V, Hagemeijer A, Boeckx N, Renard M, Wlodarska I, et al. Is there a difference in childhood T-cell acute lymphoblastic leukaemia and T-cell lymphoblastic lymphoma? Leuk Lymphoma. 2007;48(9):1745–54.

    Article  Google Scholar 

  7. Burkhardt B, Bruch J, Zimmermann M, Strauch K, Parwaresch R, Ludwig WD, et al. Loss of heterozygosity on chromosome 6q14-q24 is associated with poor outcome in children and adolescents with T-cell lymphoblastic lymphoma. Leukemia. 2006;20(8):1422–9.

    Article  CAS  Google Scholar 

  8. Lones MA, Heerema NA, Le Beau MM, Sposto R, Perkins SL, Kadin ME, et al. Chromosome abnormalities in advanced stage lymphoblastic lymphoma of children and adolescents: a report from CCG-E08. Cancer Genet Cytogenet. 2007;172(1):1–11.

    Article  CAS  Google Scholar 

  9. Sekimizu M, Sunami S, Nakazawa A, Hayashi Y, Okimoto Y, Saito AM, et al. Chromosome abnormalities in advanced stage T-cell lymphoblastic lymphoma of children and adolescents: a report from Japanese Paediatric Leukaemia/Lymphoma Study Group (JPLSG) and review of the literature. Br J Haematol. 2011;154(5):612–7.

    Article  Google Scholar 

  10. Cave H, Suciu S, Preudhomme C, Poppe B, Robert A, Uyttebroeck A, et al. Clinical significance of HOX11L2 expression linked to t(5;14)(q35;q32), of HOX11 expression, and of SIL-TAL fusion in childhood T-cell malignancies: results of EORTC studies 58881 and 58951. Blood. 2004;103(2):442–50.

    Article  CAS  Google Scholar 

  11. Baleydier F, Decouvelaere AV, Bergeron J, Gaulard P, Canioni D, Bertrand Y, et al. T cell receptor genotyping and HOXA/TLX1 expression define three T lymphoblastic lymphoma subsets which might affect clinical outcome. Clin Cancer Res. 2008;14(3):692–700.

    Article  CAS  Google Scholar 

  12. Dadi S, Le Noir S, Payet-Bornet D, Lhermitte L, Zacarias-Cabeza J, Bergeron J, et al. TLX homeodomain oncogenes mediate T cell maturation arrest in T-ALL via interaction with ETS1 and suppression of TCRalpha gene expression. Cancer Cell. 2012;21(4):563–76.

    Article  CAS  Google Scholar 

  13. Weng AP, Ferrando AA, Lee W, JPt M, Silverman LB, Sanchez-Irizarry C, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306(5694):269–71.

    Article  CAS  Google Scholar 

  14. Van Vlierberghe P, van Grotel M, Tchinda J, Lee C, Beverloo HB, van der Spek PJ, et al. The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia. Blood. 2008;111(9):4668–80.

    Article  Google Scholar 

  15. Graux C, Cools J, Melotte C, Quentmeier H, Ferrando A, Levine R, et al. Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia. Nat Genet. 2004;36(10):1084–9.

    Article  CAS  Google Scholar 

  16. Burkhardt B, Moericke A, Klapper W, Greene F, Salzburg J, Damm-Welk C, et al. Pediatric precursor T lymphoblastic leukemia and lymphoblastic lymphoma: differences in the common regions with loss of heterozygosity at chromosome 6q and their prognostic impact. Leuk Lymphoma. 2008;49(3):451–61.

    Article  CAS  Google Scholar 

  17. Bonn BR, Huge A, Rohde M, Oschlies I, Klapper W, Voss R, et al. Whole exome sequencing hints at a unique mutational profile of paediatric T-cell lymphoblastic lymphoma. Br J Haematol. 2015;168(2):308–13.

    Article  CAS  Google Scholar 

  18. Callens C, Baleydier F, Lengline E, Ben Abdelali R, Petit A, Villarese P, et al. Clinical impact of NOTCH1 and/or FBXW7 mutations, FLASH deletion, and TCR status in pediatric T-cell lymphoblastic lymphoma. J Clin Oncol. 2012;30(16):1966–73.

    Article  CAS  Google Scholar 

  19. Jun JI, Chung CW, Lee HJ, Pyo JO, Lee KN, Kim NS, et al. Role of FLASH in caspase-8-mediated activation of NF-kappaB: dominant-negative function of FLASH mutant in NF-kappaB signaling pathway. Oncogene. 2005;24(4):688–96.

    Article  CAS  Google Scholar 

  20. Alm-Kristiansen AH, Saether T, Matre V, Gilfillan S, Dahle O, Gabrielsen OS. FLASH acts as a co-activator of the transcription factor c-Myb and localizes to active RNA polymerase II foci. Oncogene. 2008;27(34):4644–56.

    Article  CAS  Google Scholar 

  21. Okuda T, Shurtleff SA, Valentine MB, Raimondi SC, Head DR, Behm F, et al. Frequent deletion of p16INK4a/MTS1 and p15INK4b/MTS2 in pediatric acute lymphoblastic leukemia. Blood. 1995;85(9):2321–30.

    CAS  PubMed  Google Scholar 

  22. Krieger D, Moericke A, Oschlies I, Zimmermann M, Schrappe M, Reiter A, et al. Frequency and clinical relevance of DNA microsatellite alterations of the CDKN2A/B, ATM and p53 gene loci: a comparison between pediatric precursor T-cell lymphoblastic lymphoma and T-cell lymphoblastic leukemia. Haematologica. 2010;95(1):158–62.

    Article  CAS  Google Scholar 

  23. Basso K, Mussolin L, Lettieri A, Brahmachary M, Lim WK, Califano A, et al. T-cell lymphoblastic lymphoma shows differences and similarities with T-cell acute lymphoblastic leukemia by genomic and gene expression analyses. Genes Chromosomes Cancer. 2011;50(12):1063–75.

    Article  CAS  Google Scholar 

  24. Sulong S, Moorman AV, Irving JA, Strefford JC, Konn ZJ, Case MC, et al. A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups. Blood. 2009;113(1):100–7.

    Article  CAS  Google Scholar 

  25. Lowe SW, Sherr CJ. Tumor suppression by Ink4a-Arf: progress and puzzles. Curr Opin Genet Dev. 2003;13(1):77–83.

    Article  CAS  Google Scholar 

  26. Volanakis EJ, Boothby MR, Sherr CJ. Epigenetic regulation of the Ink4a-Arf (Cdkn2a) tumor suppressor locus in the initiation and progression of Notch1-driven T cell acute lymphoblastic leukemia. Exp Hematol. 2013;41(4):377–86.

    Article  CAS  Google Scholar 

  27. Di Cello F, Dhara S, Hristov AC, Kowalski J, Elbahloul O, Hillion J, et al. Inactivation of the Cdkn2a locus cooperates with HMGA1 to drive T-cell leukemogenesis. Leuk Lymphoma. 2013;54(8):1762–8.

    Article  Google Scholar 

  28. Sanchez-Martin M, Ferrando A. The NOTCH1-MYC highway toward T-cell acute lymphoblastic leukemia. Blood. 2017;129(9):1124–33.

    Article  CAS  Google Scholar 

  29. Thompson BJ, Buonamici S, Sulis ML, Palomero T, Vilimas T, Basso G, et al. The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia. J Exp Med. 2007;204(8):1825–35.

    Article  CAS  Google Scholar 

  30. Park MJ, Taki T, Oda M, Watanabe T, Yumura-Yagi K, Kobayashi R, et al. FBXW7 and NOTCH1 mutations in childhood T cell acute lymphoblastic leukaemia and T cell non-Hodgkin lymphoma. Br J Haematol. 2009;145(2):198–206.

    Article  CAS  Google Scholar 

  31. Palomero T, Dominguez M, Ferrando AA. The role of the PTEN/AKT pathway in NOTCH1-induced leukemia. Cell Cycle. 2008;7(8):965–70.

    Article  CAS  Google Scholar 

  32. Balbach ST, Makarova O, Bonn BR, Zimmermann M, Rohde M, Oschlies I, et al. Proposal of a genetic classifier for risk group stratification in pediatric T-cell lymphoblastic lymphoma reveals differences from adult T-cell lymphoblastic leukemia. Leukemia. 2016;30(4):970–3.

    Article  CAS  Google Scholar 

  33. Roncero AM, Lopez-Nieva P, Cobos-Fernandez MA, Villa-Morales M, Gonzalez-Sanchez L, Lopez-Lorenzo JL, et al. Contribution of JAK2 mutations to T-cell lymphoblastic lymphoma development. Leukemia. 2016;30(1):94–103.

    Article  CAS  Google Scholar 

  34. Strehl S, Nebral K, Konig M, Harbott J, Strobl H, Ratei R, et al. ETV6-NCOA2: a novel fusion gene in acute leukemia associated with coexpression of T-lymphoid and myeloid markers and frequent NOTCH1 mutations. Clin Cancer Res. 2008;14(4):977–83.

    Article  CAS  Google Scholar 

  35. Bond J, Touzart A, Nadal N, Trinquand A, Thouvenin S, Da Cruz V, et al. Early thymic precursor-like lymphomatous presentation of the ETV6-NCOA2 translocation. Br J Haematol. 2017;181:392–4.

    Article  Google Scholar 

  36. Asnafi V, Beldjord K, Boulanger E, Comba B, Le Tutour P, Estienne MH, et al. Analysis of TCR, pT alpha, and RAG-1 in T-acute lymphoblastic leukemias improves understanding of early human T-lymphoid lineage commitment. Blood. 2003;101(7):2693–703.

    Article  CAS  Google Scholar 

  37. Spits H. Development of alphabeta T cells in the human thymus. Nat Rev Immunol. 2002;2(10):760–72.

    Article  Google Scholar 

  38. Blom B, Verschuren MC, Heemskerk MH, Bakker AQ, van Gastel-Mol EJ, Wolvers-Tettero IL, et al. TCR gene rearrangements and expression of the pre-T cell receptor complex during human T-cell differentiation. Blood. 1999;93(9):3033–43.

    CAS  PubMed  Google Scholar 

  39. Gutierrez A, Dahlberg SE, Neuberg DS, Zhang J, Grebliunaite R, Sanda T, et al. Absence of biallelic TCRgamma deletion predicts early treatment failure in pediatric T-cell acute lymphoblastic leukemia. J Clin Oncol. 2010;28(24):3816–23.

    Article  CAS  Google Scholar 

  40. Patrick K, Wade R, Goulden N, Mitchell C, Moorman AV, Rowntree C, et al. Outcome for children and young people with Early T-cell precursor acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL 2003. Br J Haematol. 2014;166(3):421–4.

    Article  CAS  Google Scholar 

  41. Wood BL, Winter SS, Dunsmore KP, Devidas M, Chen S, Asselin B, et al. T-lymphoblastic leukemia (T-ALL) shows excellent outcome, lack of significance of the early Thymic precursor (ETP) Immunophenotype, and validation of the prognostic value of end-induction minimal residual disease (MRD) in Children’s oncology group (COG) Study AALL0434. Blood. 2014;124(21):1.

    Google Scholar 

  42. Ferrando AA, Neuberg DS, Staunton J, Loh ML, Huard C, Raimondi SC, et al. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell. 2002;1(1):75–87.

    Article  CAS  Google Scholar 

  43. Soulier J, Clappier E, Cayuela JM, Regnault A, Garcia-Peydro M, Dombret H, et al. HOXA genes are included in genetic and biologic networks defining human acute T-cell leukemia (T-ALL). Blood. 2005;106(1):274–86.

    Article  CAS  Google Scholar 

  44. Homminga I, Pieters R, Langerak AW, de Rooi JJ, Stubbs A, Verstegen M, et al. Integrated transcript and genome analyses reveal NKX2-1 and MEF2C as potential oncogenes in T cell acute lymphoblastic leukemia. Cancer Cell. 2011;19(4):484–97.

    Article  CAS  Google Scholar 

  45. Raetz EA, Perkins SL, Bhojwani D, Smock K, Philip M, Carroll WL, et al. Gene expression profiling reveals intrinsic differences between T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Pediatr Blood Cancer. 2006;47(2):130–40.

    Article  Google Scholar 

  46. Mussolin L, Holmes AB, Romualdi C, Sales G, D’Amore ES, Ghisi M, et al. An aberrant microRNA signature in childhood T-cell lymphoblastic lymphoma affecting CDKN1B expression, NOTCH1 and growth factor signaling pathways. Leukemia. 2014;28(9):1909–12.

    Article  CAS  Google Scholar 

  47. Bonn BR, Rohde M, Zimmermann M, Krieger D, Oschlies I, Niggli F, et al. Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence. Blood. 2013;121(16):3153–60.

    Article  CAS  Google Scholar 

  48. Kontny U, Oschlies I, Woessmann W, Burkhardt B, Lisfeld J, Salzburg J, et al. Non-anaplastic peripheral T-cell lymphoma in children and adolescents--a retrospective analysis of the NHL-BFM study group. Br J Haematol. 2015;168(6):835–44.

    Article  CAS  Google Scholar 

  49. Kobayashi R, Yamato K, Tanaka F, Takashima Y, Inada H, Kikuchi A, et al. Retrospective analysis of non-anaplastic peripheral T-cell lymphoma in pediatric patients in Japan. Pediatr Blood Cancer. 2010;54(2):212–5.

    PubMed  Google Scholar 

  50. Windsor R, Stiller C, Webb D. Peripheral T-cell lymphoma in childhood: population-based experience in the United Kingdom over 20 years. Pediatr Blood Cancer. 2008;50(4):784–7.

    Article  Google Scholar 

  51. Mellgren K, Attarbaschi A, Abla O, Alexander S, Bomken S, Bubanska E, et al. Non-anaplastic peripheral T cell lymphoma in children and adolescents-an international review of 143 cases. Ann Hematol. 2016;95(8):1295–305.

    Article  CAS  Google Scholar 

  52. Hutchison RE, Laver JH, Chang M, Muzzafar T, Desai S, Murphy S, et al. Non-anaplastic peripheral t-cell lymphoma in childhood and adolescence: a Children’s oncology group study. Pediatr Blood Cancer. 2008;51(1):29–33.

    Article  Google Scholar 

  53. Lepretre S, Buchonnet G, Stamatoullas A, Lenain P, Duval C, d’Anjou J, et al. Chromosome abnormalities in peripheral T-cell lymphoma. Cancer Genet Cytogenet. 2000;117(1):71–9.

    Article  CAS  Google Scholar 

  54. Nelson M, Horsman DE, Weisenburger DD, Gascoyne RD, Dave BJ, Loberiza FR, et al. Cytogenetic abnormalities and clinical correlations in peripheral T-cell lymphoma. Br J Haematol. 2008;141(4):461–9.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  57. Palomero T, Couronne L, Khiabanian H, Kim MY, Ambesi-Impiombato A, Perez-Garcia A, 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  Google Scholar 

  58. Abate F, da Silva-Almeida AC, Zairis S, Robles-Valero J, Couronne L, Khiabanian H, 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  Google Scholar 

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

    Article  CAS  Google Scholar 

  60. Dobay MP, Lemonnier F, Missiaglia E, Bastard C, Vallois D, Jais JP, 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–e51.

    Article  Google Scholar 

  61. Lemonnier F, Couronne L, Parrens M, Jais JP, Travert M, Lamant L, et al. Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters. Blood. 2012;120(7):1466–9.

    Article  CAS  Google Scholar 

  62. Cairns RA, Iqbal J, Lemonnier F, Kucuk C, de Leval L, Jais JP, et al. IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. Blood. 2012;119(8):1901–3.

    Article  CAS  Google Scholar 

  63. Rohr J, Guo S, Huo J, Bouska A, Lachel C, Li Y, et al. Recurrent activating mutations of CD28 in peripheral T-cell lymphomas. Leukemia. 2016;30(5):1062–70.

    Article  CAS  Google Scholar 

  64. Vallois D, Dobay MP, Morin RD, Lemonnier F, Missiaglia E, Juilland M, 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  Google Scholar 

  65. Vasmatzis G, Johnson SH, Knudson RA, Ketterling RP, Braggio E, Fonseca R, et al. Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas. Blood. 2012;120(11):2280–9.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Systems Biology Ireland, School of Medicine, University College Dublin, Dublin, Ireland

    Jonathan Bond

  2. University College Dublin, Dublin, Ireland

    Owen Patrick Smith

  3. Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland

    Owen Patrick Smith

  4. Trinity College Dublin, Dublin, Ireland

    Owen Patrick Smith

Authors
  1. Jonathan Bond
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Owen Patrick Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Owen Patrick Smith .

Editor information

Editors and Affiliations

  1. University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada

    Oussama Abla

  2. Medical University of Vienna, St. Anna Children’s Hospital, Vienna, Wein, Austria

    Andishe Attarbaschi

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Bond, J., Smith, O.P. (2019). Pathogenesis of T-Non-Hodgkin’s Lymphoma. In: Abla, O., Attarbaschi, A. (eds) Non-Hodgkin's Lymphoma in Childhood and Adolescence. Springer, Cham. https://doi.org/10.1007/978-3-030-11769-6_5

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-11769-6_5

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-11768-9

  • Online ISBN: 978-3-030-11769-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation