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Chapter 74 Origin of Hodgkin Lymphoma 1211

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recognized (e.g., CD30 GC B cells), and it will be important to take Epstein-Barr virus-harboring Hodgkin and Reed/Sternberg cells in
these novel findings into consideration for a refinement of the cellular Hodgkin disease. Blood 96(9):3133–3138, 2000.
origin of HRS and LP cells. 12. Jones RJ, Gocke CD, Kasamon YL, et al: Circulating clonotypic B cells
The recent molecular biologic findings about HRS cells also offer in classic Hodgkin lymphoma. Blood 113(23):5920–5926, 2009.
some explanations for the typical and rather unique immunopheno- 13. Küppers R: Clonogenic B cells in classic Hodgkin lymphoma. Blood
typic heterogeneity of the HRS cells between cases and also among 114(18):3970–3971, 2009.
HRS cells of a given clone. The heterogeneity is likely due in part to 14. Vockerodt M, Soares M, Kanzler H, et al: Detection of clonal Hodgkin
different combinations of transforming events between HL cases. and Reed-Sternberg cells with identical somatically mutated and rear-
Moreover, the coexpression of multiple master regulators of different ranged VH genes in different biopsies in relapsed Hodgkin’s disease.
hematopoietic cell lineages (e.g., PAX5, ID2, NOTCH1) within one Blood 92(8):2899–2907, 1998.
HRS cell clone may cause major fluctuations in gene expression 15. Nakashima M, Ishii Y, Watanabe M, et al: The side population, as
between clone members by fluctuation of the competing transcrip- a precursor of Hodgkin and Reed-Sternberg cells and a target for
tion factors. Finally, because HRS cells are intimately interacting with nuclear factor-kappaB inhibitors in Hodgkin’s lymphoma. Cancer Sci
multiple types of cells in their microenvironment, both by cellular 101(11):2490–2496, 2010.
interactions and through cytokines and chemokines, variations in the 16. Shafer JA, Cruz CR, Leen AM, et al: Antigen-specific cytotoxic T
direct surrounding of HRS cells may cause differences in gene expres- lymphocytes can target chemoresistant side-population tumor cells in
sion in these cells. Hodgkin lymphoma. Leuk Lymphoma 51(5):870–880, 2010.
Further work is needed to fully understand the transforming 17. Küppers R, Dührsen U, Hansmann ML: Pathogenesis, diagnosis, and
events that lead to the generation of malignant HRS and LP cell treatment of composite lymphomas. Lancet Oncol 15(10):e435–e446,
clones, but with the availability of new methods, such as massive 2014.
parallel sequencing of tumor genomes, it can be expected that major 18. Bräuninger A, Schmitz R, Bechtel D, et al: Küppers R. Molecular
progresses will be made in the near future. biology of Hodgkin and Reed/Sternberg cells in Hodgkin’s lymphoma.
Finally, the recent detection of cell-free DNA presumably derived Int J Cancer 118(8):1853–1861, 2006.
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from HRS cells in the blood plasma of patients with HL offers 19. Mancao C, Hammerschmidt W: Epstein-Barr virus latent membrane
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20. Kato M, Sanada M, Kato I, et al: Frequent inactivation of A20 in B-cell
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