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The biology of Hodgkin's lymphoma

Key Points

  • Hodgkin and Reed–Sternberg (HRS) cells of classical Hodgkin's lymphoma are probably derived from germinal centre B cells that have acquired disadvantageous immunoglobulin variable chain gene mutations and normally would have undergone apoptosis, whereas lymphocytic and histiocytic (L&H) cells of NLPHL appear to derive from antigen-selected germinal centre B cells. Few cases of classical Hodgkin's lymphoma originate from T cells.

  • Classical Hodgkin's lymphoma is unique among human lymphomas in the extent to which the lymphoma cells have undergone reprogramming of gene expression. They have lost expression of most B cell-typical genes and acquired expression of multiple genes that are typical for other types of cells of the immune system.

  • Multiple signalling pathways and transcription factors show deregulated activity in HRS cells, including nuclear factor-κB, Jak–Stat, PI3K–Akt, Erk, AP1, notch 1 and receptor tyrosine kinases.

  • The transforming events involved in the generation of HRS cells are only partly understood, but several known recurrent genetic lesions involve members of the nuclear factor-κB or Jak–Stat signalling pathways.

  • HRS cells attract many cells into the lymphoma tissue, resulting in a typical inflammatory microenvironment. This environment probably promotes the survival of HRS cells and helps them to escape attack from cytotoxic T or natural killer cells.

Abstract

Hodgkin's lymphoma was first described in 1832. The aetiology of this lymphoma, however, remained enigmatic for a long time. Only within the past 10 years has the B-cell nature of the pathognomonic Hodgkin and Reed–Sternberg (HRS) cells been revealed, along with several recurrent genetic lesions. The pathogenetic role for Epstein–Barr virus infection has also been substantiated. HRS cells in classical Hodgkin's lymphoma have several characteristics that are unusual for lymphoid tumour cells, and the Hodgkin's lymphoma microenvironment is dominated by an extensive mixed, potentially inflammatory cellular infiltrate. Understanding the contribution of all of these changes to the pathogenesis of this disease is essential for the development of novel therapies.

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Figure 1: Hodgkin and Reed–Sternberg (HRS) cells in their microenvironment.
Figure 2: Reprogramming of Hodgkin and Reed–Sternberg (HRS) cells.
Figure 3: Nuclear factor-κB (NF-κB) in Hodgkin and Reed–Sternberg (HRS) cells.
Figure 4: Cellular interactions in the Hodgkin's lymphoma microenvironment.

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Acknowledgements

I am grateful to the Deutsche Forschungsgemeinschaft, the Deutsche Krebshilfe, the Wilhelm Sander Stiftung, and the Deutsche José Carreras Leukämie-Stiftung for generous support. I thank M.-L. Hansmann and all members of the group for many stimulating discussions. I apologize to all colleagues whose work could not be cited owing to space restrictions.

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Glossary

Plasma cell

A terminally differentiated B cell that is specialized for the secretion of antibodies.

Class switching

The somatic recombination process by which immunoglobulin isotypes are switched from IgM to IgG, IgA or IgE.

LMP1

(Latent membrane protein 1). An EBV-encoded protein that activates NF-κB and other factors.

LMP2A

(Latent membrane protein 2A). An EBV-encoded protein that mimics a B-cell receptor.

Endomitosis

Chromosomal replication without cell division.

Rosetting T cells

A phenomenon in which CD4+ T cells surround HRS cells in a rosette pattern.

TH1 response

A T-helper-1-cell-mediated immune response is mediated by pro-inflammatory cytokines such as IFNγ, IL-1β and TNFα. It promotes cellular immune responses against intracellular infections and malignancy.

TH2 response

A T-helper-2-cell-mediated immune response involves the production of cytokines, such as IL-4, that stimulate antibody production. TH2 cytokines promote secretory immune responses of mucosal surfaces to extracellular pathogens and allergic reactions.

Infectious mononucleosis

A self-limiting disease usually caused by a delayed primary infection with EBV in adolescents or adults.

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Küppers, R. The biology of Hodgkin's lymphoma. Nat Rev Cancer 9, 15–27 (2009). https://doi.org/10.1038/nrc2542

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