Identification of Common Germinal-Center B-Cell Precursors in Two Patients with Both Hodgkin's Disease and Non-Hodgkin's Lymphoma

Bräuninger, Andreas; Hansmann, Martin‐Leo; Strickler, John G.; Dummer, Reinhard; Burg, G; Rajewsky, Klaus; Küppers, Ralf

doi:10.1056/nejm199904223401604

Cited by 245 publications

(204 citation statements)

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“…In all informative cases of B-cell lineage cHD (41 in total) analyzed so far (Bräuninger et al, 1999a;Irsch et al, 1998;Kanzler et al, 1996aKanzler et al, , 1996bKüppers et al, 1994;Marafioti et al, 1999Marafioti et al, , 2000Müschen et al, 2000;Vockerodt et al, 1998), the H/RS cells harbor somatically mutated Ig genes with mutation frequencies of the V H genes between 2% and 23% (average 10%; Klein et al, 1998). In the H/RS cells analyzed here, only one difference from the most homologous germline gene was detected in the Ig heavy chain gene rearrangement and no mutation was detected within the two Ig light chain gene rearrangements.…”

Section: Discussionmentioning

confidence: 99%

“…In most cases of cHD, H/RS cells do not express B lineage markers, although in more than 90% of cHD cases, H/RS cells represent the outgrowth of a tumor clone derived from mature antigen-experienced B cells , and derivation of H/RS cells from the T lineage is rare (Müschen et al, 2000). This conclusion is based on the amplification of clonally related immunoglobulin (Ig) gene rearrangements from single micromanipulated H/RS cells in 45 of 46 analyzed cases (Bräuninger et al, 1999a;Irsch et al, 1998;Kanzler et al, 1996aKanzler et al, , 1996bKüppers et al, 1994;Marafioti et al, 1999Marafioti et al, , 2000Müschen et al, 2000;Ohno et al, 1998;Vockerodt et al, 1998). In all informative B-lineage cases (41 in total), the H/RS cells harbored somatically mutated variable (V) region genes, indicating their (post-) germinal center (GC) B-cell origin.…”

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confidence: 99%

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Molecular Single-Cell Analysis of Hodgkin- and Reed-Sternberg Cells Harboring Unmutated Immunoglobulin Variable Region Genes

Müschen

Küppers

Spieker

et al. 2001

Laboratory Investigation

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SUMMARY:Hodgkin-and Reed-Sternberg (H/RS) cells in classical Hodgkin's disease of the B lineage are the clonal progeny of antigen-experienced B cells harboring highly mutated immunoglobulin variable (V) region genes. Based on the detection of obviously destructive somatic mutations in a fraction of cases, we speculated that H/RS cells may be derived from a pre-apoptotic germinal center B cell. Seemingly contradicting this speculation, we present here the first case of classical Hodgkin's disease with H/RS cells harboring unmutated, potentially functional V region genes, which may indicate the derivation of the H/RS clone from a naive B cell. However, germinal center founder cells, which have not yet acquired somatic mutations, already have the intrinsic propensity to die by apoptosis. Thus, the rare occurrence of H/RS cells with unmutated V genes is expected if the H/RS cells are derived from the pool of pre-apoptotic germinal center B cells. (Lab Invest 2001, 81:289 -295).

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Molecular Single-Cell Analysis of Hodgkin- and Reed-Sternberg Cells Harboring Unmutated Immunoglobulin Variable Region Genes

Müschen

Küppers

Spieker

et al. 2001

Laboratory Investigation

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“…Moreover, HRS cells carry mutations in the Ig variable region genes, which is a hallmark of B cells that have undergone or are undergoing a germinal center reaction, in which the process of somatic hypermutation is active (5,9,10). These findings identify germinal center B cells as precursors of HRS cells, even though they lost their distinct gene expression and cell surface marker profile characteristic for normal mature B cells (5,11,12).…”

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confidence: 97%

Incomplete cytokinesis and re-fusion of small mononucleated Hodgkin cells lead to giant multinucleated Reed–Sternberg cells

Rengstl

Newrzela

Heinrich

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Multinucleated Reed-Sternberg (RS) cells are pathognomonic for classical Hodgkin lymphoma (HL), and their presence is essential for diagnosis. How these giant tumor cells develop is controversial, however. It has been postulated that RS cells arise from mononucleated Hodgkin cells via endomitosis. Conversely, continuous single-cell tracking of HL cell lines by long-term time-lapse microscopy has identified cell fusion as the main route of RS cell formation. In contrast to growth-induced formation of giant Hodgkin cells, fusion of small mononuclear cells followed by a size increase gives rise to giant RS cells. Of note, fusion of cells originating from the same ancestor, termed re-fusion, is seen nearly exclusively. In the majority of cases, re-fusion of daughter cells is preceded by incomplete cytokinesis, as demonstrated by microtubule bonds among the cells. We confirm at the level of individual tracked cells that giant Hodgkin and RS cells have little proliferative capacity, further supporting small mononuclear Hodgkin cells as the proliferative compartment of the HL tumor clone. In addition, sister cells show a shared propensity for re-fusion, providing evidence of early RS cell fate commitment. Thus, RS cell generation is related neither to cell fusion of unrelated Hodgkin cells nor to endomitosis, but rather is mediated by re-fusion of daughter cells that underwent mitosis. This surprising finding supports the existence of a unique mechanism for the generation of multinuclear RS cells that may have implications beyond HL, given that RS-like cells are frequently observed in several other lymphoproliferative diseases as well.

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“…HRS cells likely originate from germinal center B cells. HL is one of the most frequent lymphomas in the Western world and EBV-encoded RNA or protein is detected in HRS cells in up to 40% of cases [68][69]. In North America, 20%-50% of HLs are EBV+ [70][71][72], but in developing countries the percentages of EBV positivity in HL are much higher.…”

Section: Hl and Nhlmentioning

confidence: 99%

Immunotherapy against cancer-related viruses

2016

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Approximately 12% of all cancers worldwide are associated with viral infections. To date, eight viruses have been shown to contribute to the development of human cancers, including Epstein-Barr virus (EBV), Hepatitis B and C viruses, and Human papilloma virus, among others. These DNA and RNA viruses produce oncogenic effects through distinct mechanisms. First, viruses may induce sustained disorders of host cell growth and survival through the genes they express, or may induce DNA damage response in host cells, which in turn increases host genome instability. Second, they may induce chronic inflammation and secondary tissue damage favoring the development of oncogenic processes in host cells. Viruses like HIV can create a more permissive environment for cancer development through immune inhibition, but we will focus on the previous two mechanisms in this review. Unlike traditional cancer therapies that cannot distinguish infected cells from non-infected cells, immunotherapies are uniquely equipped to target virus-associated malignancies. The targeting and functioning mechanisms associated with the immune response can be exploited to prevent viral infections by vaccination, and can also be used to treat infection before cancer establishment. Successes in using the immune system to eradicate established malignancy by selective recognition of virus-associated tumor cells are currently being reported. For example, numerous clinical trials of adoptive transfer of ex vivo generated virus-specific T cells have shown benefit even for established tumors in patients with EBV-associated malignancies. Additional studies in other virus-associated tumors have also been initiated and in this review we describe the current status of immunotherapy for virus-associated malignancies and discuss future prospects.

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Identification of Common Germinal-Center B-Cell Precursors in Two Patients with Both Hodgkin's Disease and Non-Hodgkin's Lymphoma

Cited by 245 publications

References 27 publications

Molecular Single-Cell Analysis of Hodgkin- and Reed-Sternberg Cells Harboring Unmutated Immunoglobulin Variable Region Genes

Molecular Single-Cell Analysis of Hodgkin- and Reed-Sternberg Cells Harboring Unmutated Immunoglobulin Variable Region Genes

Incomplete cytokinesis and re-fusion of small mononucleated Hodgkin cells lead to giant multinucleated Reed–Sternberg cells

Immunotherapy against cancer-related viruses

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