Cell fusion is not involved in the generation of giant cells in the Hodgkin‐Reed Sternberg cell line L1236

Ré, Daniel; Benenson, Elena; Beyer, Marc; Gresch, Oliver; Draube, Andreas; Diehl, Volker; Wolf, Jürgen

doi:10.1002/ajh.1068

Cited by 16 publications

(12 citation statements)

References 11 publications

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“…Apart from a few studies investigating the proliferation potential of RS cells (13,14,28), the giant cell population has not been characterized in detail up to now. Most previous functional studies used the bulk of HL cell lines, ignoring cellular heterogeneity (18,(29)(30)(31). Tracking of individual HRS cells and their progeny over time has allowed us to dissect giant cell dynamics within the heterogeneous cultures of three HL cell lines and to link HRS cell behavior, RS cell development, and the future fate of these cells.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, a mixing experiment of dual fluorescent-labeled cells of the HL cell line L1236 provided evidence against cell fusion as the mechanism giving rise to RS cells (18). Thus, endomitosis instead of cell fusion has been proposed as the mechanism for RS cell formation in HL (17,18). But endomitosis by definition means mitosis leading to polyploidy within a cell without nuclear division, and thus the proposed mechanism should have been…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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“…27,28 Genetic instability, including complex cytogenetic aberrations, is well documented in H and RS cells 10,29,30 but it is still unclear whether these markers develop as an epiphenomenon secondary to still unknown initial transformation events or represent well-defined events in tumorigenesis (reviewed by Re et al 31 ). Telomerase activation, which is a hallmark of malignant tumors 32 and thought to be a late event in multistage tumorigenesis, 33 was first identified in HD by Brousset et al…”

Section: Discussionmentioning

confidence: 99%

The 3D nuclear organization of telomeres marks the transition from Hodgkin to Reed–Sternberg cells

et al. 2008

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To get an insight into the transition from mononuclear Hodgkin cells (H cells) to diagnostic multinuclear Reed-Sternberg cells (RS cells), we performed an analysis of the three-dimensional (3D) structure of the telomeres in the nuclei of the Hodgkin cell lines HDLM-2, L-428, L-1236 and lymph node biopsies of patients with Hodgkin's disease. Cellular localization of key proteins of the telomere-localized shelterin complex, the mitotic spindle and double-stranded DNA breaks was also analyzed. RS cells show significantly shorter and significantly fewer telomeres in relation to the total nuclear volume when compared with H cells; in particular, telomere-poor 'ghost' nuclei are often adjacent to one or two nuclei displaying huge telomeric aggregates. Shelterin proteins are mainly cytoplasmic in both H and RS cells, whereas double-stranded DNA breaks accumulate in the nuclei of RS cells. In RS cells, multipolar spindles prevent proper chromosome segregation. In conclusion, a process of nuclear disorganization seems to initiate in H cells and further progresses when the cells turn into RS cells and become end-stage tumor cells, unable to divide further because of telomere loss, shortening and aggregate formation, extensive DNA damage and aberrant mitotic spindles that may no longer sustain chromosome segregation. Our findings allow a mechanistic 3D understanding of the transition of H to RS cells.

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“…This could partly explain the controversy between the high proliferation-associated protein expression in HRSC and the lack of efficient tumor cell accumulation. In addition to multinucleation, which is not due to cellular fusion [192,193] , Hodgkin cells are near tetraploid, and almost all HRSC show rather random numerical chromosomal aberrations [194][195][196] , with multinucleation, poly-and aneuploidy being explainable by cytokinesis defects in HRSC. Interestingly, HRSC show profound deregulation of cell cycle checkpoints [20,174,188,197,198] .…”

Section: Cell Cycle Deregulationmentioning

confidence: 99%

Pathobiology of Classical Hodgkin Lymphoma

Tzankov

Dirnhofer

2006

Pathobiology

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The World Health Organization has acknowledged the malignant nature of classical Hodgkin lymphoma (cHL), which encompasses four histological subtypes. The diagnosis of cHL is based on the detection of malignant Hodgkin and Reed-Sternberg cells (HRSC) confirmed by immunophenotyping and the detection of growth patterns specific to each histological subtype. The pathologic HRSC arise from germinal center or immediate postgerminal cells that lack detectable immunoglobulin/B-cell antigen receptor expression, with a consequent loss of B-cell identity; very few cHL cases are of T-cell origin. To escape apoptosis, which normally occurs in B cells with nonfunctioning antigen receptor machinery, HRSC develop concurrent antiapoptotic mechanisms by activation of nuclear factor-ĸB or are rescued by Epstein-Barr virus infection. HRSC are characterized by a variable and inconstant immunophenotype, with a remarkable loss of lineage-specific cell antigens and expression of antigens of other cell lineages. The master plan of B-cell identity in HRSC is disturbed not only at the immunoglobulin expression level, but also at the transcriptional factor level. HRSC are further characterized by profound cell cycle deregulation with futile replication, multinucleation and poly- and aneuploidy. Here, we review pathobiological aspects of cHL with respect to lymphomagenesis and routine diagnostics.

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Cell fusion is not involved in the generation of giant cells in the Hodgkin‐Reed Sternberg cell line L1236

Cited by 16 publications

References 11 publications

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

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

The 3D nuclear organization of telomeres marks the transition from Hodgkin to Reed–Sternberg cells

Pathobiology of Classical Hodgkin Lymphoma

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