Incomplete cytokinesis and re-fusion of small mononucleated Hodgkin cells lead to giant multinucleated Reed–Sternberg cells
Open Access
- 3 December 2013
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 110 (51), 20729-20734
- https://doi.org/10.1073/pnas.1312509110
Abstract
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. Significance Multinucleated giant tumor cells are frequently observed in tissue sections of patients with cancer. In classical Hodgkin lymphoma (HL), these so-called Reed–Sternberg (RS) cells are pathognomonic for the disease. Despite the well-described disease-promoting functions of multinucleated RS cells, their development remains obscure. Long-term time-lapse microscopy and single-cell tracking of HL cell lines demonstrated that RS cells are generated by re-fusion of small mononuclear progenitors. Importantly, fusing cells share almost exclusively the same ancestor, and visualization of the microtubule network revealed a persistent connection between daughter cells in the majority of re-fusion events. Understanding the mechanisms involved in fusion-based RS cell development will further illuminate giant tumor cell formation and may lead to new therapeutic intervention strategies.Keywords
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