Human CD30+ B cells represent a unique subset related to Hodgkin lymphoma cells
Marc A. Weniger, … , Martin-Leo Hansmann, Ralf Küppers
Marc A. Weniger, … , Martin-Leo Hansmann, Ralf Küppers
Published July 2, 2018; First published June 11, 2018
Citation Information: J Clin Invest. 2018;128(7):2996-3007. https://doi.org/10.1172/JCI95993.
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Research Article Hematology Immunology

Human CD30+ B cells represent a unique subset related to Hodgkin lymphoma cells

Abstract

Very few B cells in germinal centers (GCs) and extrafollicular (EF) regions of lymph nodes express CD30. Their specific features and relationship to CD30-expressing Hodgkin and Reed/Sternberg (HRS) cells of Hodgkin lymphoma are unclear but highly relevant, because numerous patients with lymphoma are currently treated with an anti-CD30 immunotoxin. We performed a comprehensive analysis of human CD30+ B cells. Phenotypic and IgV gene analyses indicated that CD30+ GC B lymphocytes represent typical GC B cells, and that CD30+ EF B cells are mostly post-GC B cells. The transcriptomes of CD30+ GC and EF B cells largely overlapped, sharing a strong MYC signature, but were strikingly different from conventional GC B cells and memory B and plasma cells, respectively. CD30+ GC B cells represent MYC+ centrocytes redifferentiating into centroblasts; CD30+ EF B cells represent active, proliferating memory B cells. HRS cells shared typical transcriptome patterns with CD30+ B cells, suggesting that they originate from these lymphocytes or acquire their characteristic features during lymphomagenesis. By comparing HRS to normal CD30+ B cells we redefined aberrant and disease-specific features of HRS cells. A remarkable downregulation of genes regulating genomic stability and cytokinesis in HRS cells may explain their genomic instability and multinuclearity.

Authors

Marc A. Weniger, Enrico Tiacci, Stefanie Schneider, Judith Arnolds, Sabrina Rüschenbaum, Janine Duppach, Marc Seifert, Claudia Döring, Martin-Leo Hansmann, Ralf Küppers

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Figure 5

Scenarios for the generation of normal CD30+ B cells and HRS cells.

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Scenarios for the generation of normal CD30+ B cells and HRS cells. (A) ...
(A) The key features of CD30+ GC B cells as outlined in the text indicate that CD30+ GC B cells represent the positively selected centrocytes (CC) that are preparing to return to the dark zone to become centroblasts (CB) again and undergo an additional round of proliferation and selection. High activity of MYC and E2F and signatures for AP-1 activity are hallmarks of these cells. CD30+ EF B cells likely represent reactivated memory B cells that undergo proliferation before they presumably differentiate into plasma cells. It is unclear whether CD30+ GC B cells may also directly differentiate into CD30+ EF B cells. (B) Scenario for the generation of HRS cells. Genetic features of HRS cells (crippled IgV genes in at least a quarter of cases) strongly indicate that these cells derive from preapoptotic GC B cells that were rescued from apoptosis by some transforming events (e.g., EBV infection in a fraction of cases). The similarities in their gene expression between HRS and CD30+ B cells indicate that HRS precursor cells differentiated into the direction of CD30+ B cells in the course of their further malignant transformation. Mainly because of the downregulation of GC B cell–specific genes and the strong constitutive NF-κB activity, HRS cells more closely resemble CD30+ EF B cells than CD30+ GC B cells.