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

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.

CD20 role in pathophysiology of Hodgkin’s disease

“…In addition to these malignant cells, HL infiltrates comprise T cells, neutrophils, eosinophils, macrophages, fibroblast, plasma cells and mast cells. 1,2 The malignant cells are referred to as giant cells, also denominated Hodgkin Reed-Sternberg (HRS) cells, and their origin remains controversial. 1 Some theories point to either a fusion of B and non-B cells or mutation in germinal-center cells and loss of B cell receptor expression.…”

“…1,2 The malignant cells are referred to as giant cells, also denominated Hodgkin Reed-Sternberg (HRS) cells, and their origin remains controversial. 1 Some theories point to either a fusion of B and non-B cells or mutation in germinal-center cells and loss of B cell receptor expression. 1,3,4 HRS cells seem to be dependent on both extracellular signals and endogenous signals derived from its own genome mutation.…”

“…1 Some theories point to either a fusion of B and non-B cells or mutation in germinal-center cells and loss of B cell receptor expression. 1,3,4 HRS cells seem to be dependent on both extracellular signals and endogenous signals derived from its own genome mutation. Macrophages may play a role in tumor support.…”

Pathobiology of Hodgkin Lymphoma

“…The immunophenotype and the genetic features of HL and HRS cells are identical in these subtypes, but their clinical characteristics and association with EBV are different. How HRS cells develop is controversial and obscure; it has been postulated that these cells arise from mononucleated Hodgkin cells via endomitosis; however recently Rengstl et al by tracking the cells and their progeny for multiple generations demonstrated that the fusion of daughter cells, termed re-fusion, plays an essential role in the formation of HRS cells in HL cell lines 20. Importantly, cell fusion events occur almost exclusively between cells sharing the same ancestor and visualization of the microtubule network in time-lapse microscopy experiments revealed a persistent connection between daughter cells in the majority of re-fusion events 20.…”

Insulin-like growth factor I is expressed in classical and nodular lymphocyte-predominant Hodgkin’s lymphoma tumour and microenvironmental cells

“…Note the observed higher density of the IGF-1R in the present study in the mononuclear Hodgkin cells as compared with the multinuclear RS cells I and the IGF-1R, with stronger expression of the IGF-1R in the mononuclear Hodgkin than in the RS cells, should foster future studies. This is particularly pertinent because the enigmatic origin of the multinuclear RS cells has recently been illuminated by the findings that they arise by the re-fusion of daughter cells from small mononuclear Hodgkin cells that have undergone mitosis and constitute the proliferative compartment of the cHL tumour clone (Rengstl et al 2013).…”