The Transition between Telomerase and ALT Mechanisms in Hodgkin Lymphoma and Its Predictive Value in Clinical Outcomes

International audienceBackground: We analyzed telomere maintenance mechanisms (TMMs) in lymph node samples from HL patients treated with standard therapy. The TMMs correlated with clinical outcomes of patients. Materials and Methods: Lymph node biopsies obtained from 38 HL patients and 24 patients with lymphadenitis were included in this study. Seven HL cell lines were used as in vitro models. Telomerase activity (TA) was assessed by TRAP assay and verified through hTERT immunofluorescence expression; alternative telomere lengthening (ALT) was also assessed, along with EBV status. Results: Both TA and ALT mechanisms were present in HL lymph nodes. Our findings were reproduced in HL cell lines. The highest levels of TA were expressed in CD30−/CD15− cells. Small cells were identified with ALT and TA. Hodgkin and Reed Sternberg cells contained high levels of PML bodies, but had very low hTERT expression. There was a significant correlation between overall survival (p < 10−3), event-free survival (p < 10−4), and freedom from progression (p < 10−3) and the presence of an ALT profile in lymph nodes of EBV+ patients. Conclusion: The presence of both types of TMMs in HL lymph nodes and in HL cell lines has not previously been reported. TMMs correlate with the treatment outcome of EBV+ HL patients

Phylogeny of seven Bulinus species originating from endemic areas in three African countries, in relation to the human blood fluke Schistosoma haematobium.

International audienceBackgroundSnails species belonging to the genus Bulinus (Planorbidae) serve as intermediate host for flukes belonging to the genus Schistosoma (Digenea, Platyhelminthes). Despite its importance in the transmission of these parasites, the evolutionary history of this genus is still obscure. In the present study, we used the partial mitochondrial cytochrome oxidase subunit I (cox1) gene, and the nuclear ribosomal ITS, 18S and 28S genes to investigate the haplotype diversity and phylogeny of seven Bulinus species originating from three endemic countries in Africa (Cameroon, Senegal and Egypt).ResultsThe cox1 region showed much more variation than the ribosomal markers within Bulinus sequences. High levels of genetic diversity were detected at all loci in the seven studied species, with clear segregation between individuals and appearance of different haplotypes, even within same species from the same locality. Sequences clustered into two lineages; (A) groups Bulinus truncatus, B. tropicus, B. globosus and B. umbilicatus; while (B) groups B. forskalii, B. senegalensis and B. camerunensis. Interesting patterns emerge regarding schistosome susceptibility: Bulinus species with lower genetic diversity are predicted to have higher infection prevalence than those with greater diversity in host susceptibility.ConclusionThe results reported in this study are very important since a detailed understanding of the population genetic structure of Bulinus is essential to understand the epidemiology of many schistosome parasites

18S-sequences

This file covers all the 18S sequences for six Bulinus species (B. truncatus, B. tropicus, B. globosus, B. umbilicatus, B. senegalensis, and B. forskalii) collected from three African counties (Cameroon, Senegal and Egypt). They were sequenced using an ABI Prism BigDye® Terminator v1.1 Cycle Sequencing Ready Reaction Kit (PE, Applied Biosystems), and were aligned using ClustalX in Mega6

Data from: Phylogeny of seven Bulinus species originating from endemic areas in three African countries, in relation to the human blood fluke Schistosoma haematobium

Background: Snails species belonging to the genus Bulinus (Planorbidae) serve as intermediate host for flukes belonging to the genus Schistosoma (Digenea, Platyhelminthes). Despite its importance in the transmission of these parasites, the evolutionary history of this genus is still obscure. In the present study, we used the partial mitochondrial cytochrome oxidase subunit I (cox1) gene, and the nuclear ribosomal ITS, 18S and 28S genes to investigate the haplotype diversity and phylogeny of seven Bulinus species originating from three endemic countries in Africa (Cameroon, Senegal and Egypt). Results: The cox1 region showed much more variation than the ribosomal markers within Bulinus sequences. High levels of genetic diversity were detected at all loci in the seven studied species, with clear segregation between individuals and appearance of different haplotypes, even within same species from the same locality. Sequences clustered into two lineages; (A) groups Bulinus truncatus, B. tropicus, B. globosus and B. umbilicatus; while (B) groups B. forskalii, B. senegalensis and B. camerunensis. Interesting patterns emerge regarding schistosome susceptibility: Bulinus species with lower genetic diversity are predicted to have higher infection prevalence than those with greater diversity in host susceptibility. Conclusion: The results reported in this study are very important since a detailed understanding of the population genetic structure of Bulinus is essential to understand the epidemiology of many schistosome parasites

Benefit of an association of an antioxidative substrate and a traditional chinese medicine on telomere elongation

Telomere shortening is involved in age-related disorders, such as cancer and cardiovascular diseases. Recently, telomerase re-activation strategies have been proposed to counteract telomere shortening and its consequences. Here, we investigated the benefit of dietary supplementation with a mix of S-adenosyl-methionine (SAMe) and a polysaccharide extract of Astragalus (APS) on telomere length of circulating lymphocytes of healthy volunteers. Blood lymphocytes of a cohort of 26 healthy volunteers who were administrated the mix of SAMe and APS in a food supplement for one year were collected. In vitro treatment of blood lymphocytes of healthy volunteers with the mix was also performed. A cohort of 150 healthy volunteers was used as a control. Telomere length was measured by Q-FISH. The micronucleus assay was performed to detect genotoxicity of the mix. The telomeres of circulating lymphocytes of the cohort of 26 donors supplemented with the mix were significantly longer than those of matched controls (p < 10-4). This elongation was essentially observed in the lymphocytes of older donors. Similarly, in vitro treatment of circulating lymphocytes with the mix significantly increased telomere length and decrease the proportion of cells with short telomeres. Here, we observed an increase in telomere length after in vivo and in vitro administration of a mix with SAMe and APS. The benefit of dietary supplementation with this mix opens a new horizon for the battle against aging and could be used in the treatment of chronic age-related disorders

Cox1 Asmit region sequences

This file covers all the cox1 (Asmit region) haplotypes for seven Bulinus species (B. truncatus, B. tropicus, B. globosus, B. umbilicatus, B. senegalensis, B. camerunensis and B. forskalii) collected from three African counties (Cameroon, Senegal and Egypt). They were sequenced using an ABI Prism BigDye® Terminator v1.1 Cycle Sequencing Ready Reaction Kit (PE, Applied Biosystems), and were aligned using ClustalX in Mega6

28S-sequences

This file covers all the 28S sequences for six Bulinus species (B. truncatus, B. tropicus, B. globosus, B. umbilicatus, B. senegalensis, and B. forskalii) collected from three African counties (Cameroon, Senegal and Egypt). They were sequenced using an ABI Prism BigDye® Terminator v1.1 Cycle Sequencing Ready Reaction Kit (PE, Applied Biosystems), and were aligned using ClustalX in Mega6

Cox1-Folmer region sequences

This file covers all the cox1 (Folmer region) haplotypes for seven Bulinus species (B. truncatus, B. tropicus, B. globosus, B. umbilicatus, B. senegalensis, B. camerunensis and B. forskalii) collected from three African counties (Cameroon, Senegal and Egypt). They were sequenced using an ABI Prism BigDye® Terminator v1.1 Cycle Sequencing Ready Reaction Kit (PE, Applied Biosystems), and were aligned using ClustalX in Mega6

Independent Mechanisms Lead to Genomic Instability in Hodgkin Lymphoma: Microsatellite or Chromosomal Instability †

Background: Microsatellite and chromosomal instability have been investigated in Hodgkin lymphoma (HL). Materials and Methods: We studied seven HL cell lines (five Nodular Sclerosis (NS) and two Mixed Cellularity (MC)) and patient peripheral blood lymphocytes (100 NS-HL and 23 MC-HL). Microsatellite instability (MSI) was assessed by PCR. Chromosomal instability and telomere dysfunction were investigated by FISH. DNA repair mechanisms were studied by transcriptomic and molecular approaches. Results: In the cell lines, we observed high MSI in L428 (4/5), KMH2, and HDLM2 (3/5), low MSI in L540, L591, and SUP-HD1, and none in L1236. NS-HL cell lines showed telomere shortening, associated with alterations of nuclear shape. Small cells were characterized by telomere loss and deletion, leading to chromosomal fusion, large nucleoplasmic bridges, and breakage/fusion/bridge (B/F/B) cycles, leading to chromosomal instability. The MC-HL cell lines showed substantial heterogeneity of telomere length. Intrachromosmal double strand breaks induced dicentric chromosome formation, high levels of micronucleus formation, and small nucleoplasmic bridges. B/F/B cycles induced complex chromosomal rearrangements. We observed a similar pattern in circulating lymphocytes of NS-HL and MC-HL patients. Transcriptome analysis confirmed the differences in the DNA repair pathways between the NS and MC cell lines. In addition, the NS-HL cell lines were radiosensitive and the MC-cell lines resistant to apoptosis after radiation exposure. Conclusions: In mononuclear NS-HL cells, loss of telomere integrity may present the first step in the ongoing process of chromosomal instability. Here, we identified, MSI as an additional mechanism for genomic instability in HL

Erratum: Cuceu, C., et al. Independent Mechanisms Lead to Genomic Instability in Hodgkin Lymphoma: Microsatellite or Chromosomal Instability. <i>Cancers</i> 2018, <i>10</i>, 233

The authors wish to make the following corrections to this paper [...