Mutations in a gene encoding a midbody protein in binucleated Reed-Sternberg cells of Hodgkin lymphoma

Krem, Maxwell M.; Salipante, Stephen J.; Horwitz, Marshall S.

doi:10.4161/cc.9.4.10780

Cited by 11 publications

(6 citation statements)

References 61 publications

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“…3). In line with this finding, a germ line mutation and a functionally relevant single nucleotide polymorphism for the gene of the midbody protein KLHDC8B in HL were reported recently (34,35). Furthermore, down-regulation of this gene in HeLa cells caused increased frequencies of binucleated cells owing to incomplete cytokinesis (36).…”

Section: Discussionsupporting

confidence: 49%

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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: Discussionsupporting

confidence: 49%

“…Identifying the underlying pathogenetic mechanism is essential. As mentioned above, an altered function of KLHDC8B might play a role (34)(35)(36). However, in a few cases we could not clearly discern whether cytokinesis was incomplete before re-fusion, because the connecting midbody had been disassembled.…”

Section: Discussionmentioning

confidence: 75%

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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“…In concordance, mutations of the midbody protein KLHDC8B in HL were recently reported. 26 , 27 Furthermore, downregulation of this gene in HeLa cells induced increased frequencies of binucleated cells. 28 Therefore, upcoming studies will address the functional role of midbody-associated proteins in HRS cells to further illuminate the molecular basis of the described re-fusion phenomenon.…”

Section: Discussionmentioning

confidence: 98%

On the origin of giant cells in Hodgkin lymphoma

Rengstl

Rieger

Newrzela

2014

Communicative & Integrative Biology

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Multinucleated giant tumor cells are frequently observed in tissue sections of lymphoma patients. In Hodgkin lymphoma (HL), these cells are pathognomonic for the disease and named Reed-Sternberg (RS) cells. Despite the well-described disease-promoting functions of RS cells, their development has remained obscure. We addressed this open question by continuous live cell imaging to observe the generation of RS cells. Single-cell tracking of HL cell lines revealed that RS cells develop from mononucleated progenitors that divide and subsequently re-fuse, before they grow and become multinucleated giant cells. Thus, RS cell generation is neither due to cell fusion of unrelated Hodgkin cells nor to endomitosis, as previously suggested. In the majority of cases, re-fusion of daughter cells was preceded by an incomplete cytokinesis, visualized by a persistent microtubule bridge connecting the cells. This surprising finding describes a novel mechanism for the formation of multinuclear giant cells with potential relevance beyond HL.

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“…Meat quality index was negatively correlated with expression of the third exon of KLHDC8B ( Fig 5H ) and this gene is associated with some cases of classical Hodgkin lymphoma which is characterized by binucleated cells. The KLHDC8B gene encodes a midbody kelch protein required during mitotic cytokinesis [ 85 , 86 ]. The third KLHDC8B exon is included in both annotated isoforms ( S4 Fig ) suggesting that additional isoforms involving this exon may be still uncovered.…”

Section: Discussionmentioning

confidence: 99%

RNA-seq analysis identifies cytoskeletal structural genes and pathways for meat quality in beef

et al. 2020

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RNA sequencing (RNA-seq) has allowed for transcriptional profiling of biological systems through the identification of differentially expressed (DE) genes and pathways. A total of 80 steers with extreme phenotypes were selected from the University of Florida multibreed Angus-Brahman herd. The average slaughter age was 12.91±8.69 months. Tenderness, juiciness and connective tissue assessed by sensory panel, along with marbling, Warner-Bratzler Shear Force (WBSF) and cooking loss, were measured in longissimus dorsi muscle. Total RNA was extracted from muscle and one RNA-seq library per sample was constructed, multiplexed, and sequenced based on protocols by Illumina HiSeq-3000 platform to generate 2×101 bp paired-end reads. The overall read mapping rate using the Btau_4.6.1 reference genome was 63%. A total of 8,799 genes were analyzed using two different methodologies, an expression association and a DE analysis. A gene and exon expression association analysis was carried out using a meat quality index on all 80 samples as a continuous response variable. The expression of 208 genes and 3,280 exons from 1,565 genes was associated with the meat quality index (p-value ≤ 0.05). A gene and isoform DE evaluation was performed analyzing two groups with extreme WBSF, tenderness and marbling. A total of 676 (adjusted p-value≤0.05), 70 (adjusted p-value≤0.1) and 198 (adjusted p-value≤0.1) genes were DE for WBSF, tenderness and marbling, respectively. A total of 106 isoforms from 98 genes for WBSF, 13 isoforms from 13 genes for tenderness and 43 isoforms from 42 genes for marbling (FDR≤0.1) were DE. Cytoskeletal and transmembrane anchoring genes and pathways were identified in the expression association, DE and the gene enrichment analyses; these proteins can have a direct effect on meat quality. Cytoskeletal proteins and transmembrane anchoring molecules can influence meat quality by allowing cytoskeletal interaction with myocyte and organelle membranes, contributing to cytoskeletal structure and architecture maintenance postmortem.

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Mutations in a gene encoding a midbody protein in binucleated Reed-Sternberg cells of Hodgkin lymphoma

Cited by 11 publications

References 61 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

On the origin of giant cells in Hodgkin lymphoma

RNA-seq analysis identifies cytoskeletal structural genes and pathways for meat quality in beef

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