Publications by authors named "Julie Rivière"

42 Publications

A framework for multicriteria decision-aid analyses in animal health surveillance applied to periodic screening for French bovine tuberculosis.

Transbound Emerg Dis 2021 Apr 4. Epub 2021 Apr 4.

Anses, Ecole nationale vétérinaire d'Alfort, Laboratoire de Santé animale USC EPIMAI, Maisons-Alfort, France.

In animal health surveillance, decision-makers must allocate limited financial and human resources, choosing appropriate protocols that consider technical, economic and human aspects (i.e. test sensitivity, cost benefits and policy acceptability respectively). Choosing in an objective manner and considering all these criteria can be challenging, especially where criteria have a tendency to be at odds with one another. In France, there are several mandatory protocols implemented to screen for bovine tuberculosis (TB), each with advantages and drawbacks concerning effectiveness, cost and acceptability. Previous studies have developed scenario tree models in order to evaluate mandatory periodic screening protocols and alternative protocols. Using these previously developed models, we estimated protocol sensitivity, costs at the level of State and farmer, probability of false suspects, and probability of culling an uninfected animal, which influence stakeholders' acceptability. We then assessed the level of difficulty for protocol implementation for veterinarians, farmers and State through the use of surveys. Using these criteria, we rank the protocols with the PROMETHEE method, a multicriteria decision-aid method, by considering the relative importance of each criterion from the decision-maker point of view in four administrative areas with contrasting epidemiological context. This method can be considered a tool to aid decision-makers in choosing the appropriate protocol to apply to a heard while considering the technical and socio-economic facets of the problem. Additionally, by adapting the criteria to specific issues with regards to decision-making, there is potential for applying the PROMETHEE method to other animal health surveillance problems.
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http://dx.doi.org/10.1111/tbed.14091DOI Listing
April 2021

Relative Contribution of Each Component of the French Ante-Mortem Surveillance System for Bovine Tuberculosis in Its Overall Sensitivity.

Microorganisms 2021 Mar 19;9(3). Epub 2021 Mar 19.

Anses, Ecole Nationale Vétérinaire d'Alfort, Laboratoire de Santé Animale, USC EPIMAI, F-94700 Maisons-Alfort, France.

The aim of this study was to assess the contribution to the sensitivity of the French ante-mortem surveillance system for bovine tuberculosis in cattle of each of the system's components (periodic screening, epidemiological investigations, and screening exchanged animals), on a local scale defined by administrative areas. These components were individually assessed in previous studies by scenario tree modeling. We used scenario tree modeling at the herd level and combined the results to evaluate the overall sensitivity of the ante-mortem surveillance system. The probability to detect at least one infected herd was consistent with the location of the outbreaks detected in 2016. In areas with a high apparent incidence, the probability of an infected herd to be detected was satisfactory (for an infected herd there was a 100% probability to be detected over a two-year period). Periodic screening was the most important component for the overall sensitivity in infected areas. In other areas, where periodic screening had stopped, tracing-on epidemiological investigation was the most sensitive component of the system. Screening exchanged animals had a negligible part in the overall sensitivity of the surveillance system.
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http://dx.doi.org/10.3390/microorganisms9030643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003711PMC
March 2021

Management practices of dog and cat owners in France (pet traveling, animal contact rates and medical monitoring): Impacts on the introduction and the spread of directly transmitted infectious pet diseases.

Transbound Emerg Dis 2021 Mar 31. Epub 2021 Mar 31.

Anses, Ecole nationale vétérinaire d'Alfort, Laboratoire de Santé Animale USC EPIMAI, Maisons-Alfort, France.

A number of owner practices among the pet dog and cat population can influence the dynamics of directly transmitted infectious dog and cat diseases, including zoonotic ones. To better depict these management practices, which include pet traveling, contact rates with other companion animals and their medical monitoring (which herein includes prevention aspects), we surveyed 2,122 dog- and/or cat-owning French households through an anonymous online questionnaire. Trips with dogs within the European Union (EU) were frequent, while cats travelled less frequently within the EU and both cats and dogs travelled less frequently outside the EU. Recurrent illegal trips with dogs and cats (non-compliant with regulatory measures) were observed in a context of non-systematic pet border controls. We found that a large proportion of dogs are taken for walks in metropolitan France, with frequent intraspecific contacts (1.4 contacts/day on average), but only a minority (1.4%) of dogs were allowed to roam freely. On the other hand, 59.7% of cat owners allowed their cats to roam freely. We classified pet owners according to different profiles, some of which may be considered 'at risk' for directly transmitted infectious pet diseases. Indeed, one dog owner profile and one cat owner profile depict 'spreaders' of pet diseases (high connectivity with other individuals, little medical monitoring but no traveling) and another dog owner profile describes a potential 'introducer' and 'spreader' of pet diseases (foreign travel, high connectivity with other individuals, and intermediate medical monitoring). While these 'at risk' profiles represent only a minority of French pet owners, they should be better characterized to reinforce targeted prevention designed to minimize the risk of (re)introduction and (re)emergence of directly transmitted infectious dog and cat diseases in France, especially when considering zoonoses with a significant potential impact, such as rabies.
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http://dx.doi.org/10.1111/tbed.14088DOI Listing
March 2021

Serial transplantation unmasks galectin-9 contribution to tumor immune escape in the MB49 murine model.

Sci Rep 2021 Mar 4;11(1):5227. Epub 2021 Mar 4.

CNRS, UMR 9018, Gustave Roussy and Université Paris-Saclay, 39 Rue Camille Desmoulins, F-94805, Villejuif, France.

Mechanisms of tumor immune escape are quite diverse and require specific approaches for their exploration in syngeneic tumor models. In several human malignancies, galectin-9 (gal-9) is suspected to contribute to the immune escape. However, in contrast with what has been done for the infiltrating cells, the contribution of gal-9 produced by malignant cells has never been demonstrated in an animal model. Therefore, we derived isogenic clones-either positive or negative for gal-9-from the MB49 murine bladder carcinoma cell line. A progressive and consistent reduction of tumor growth was observed when gal-9-KO cells were subjected to serial transplantations into syngeneic mice. In contrast, tumor growth was unaffected during parallel serial transplantations into nude mice, thus linking tumor inhibition to the enhancement of the immune response against gal-9-KO tumors. This stronger immune response was at least in part explained by changing patterns of response to interferon-γ. One consistent change was a more abundant production of CXCL10, a major inflammatory factor whose production is often induced by interferon-γ. Overall, these observations demonstrate for the first time that serial transplantation into syngeneic mice can be a valuable experimental approach for the exploration of novel mechanisms of tumor immune escape.
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http://dx.doi.org/10.1038/s41598-021-84270-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933353PMC
March 2021

Analysis of Polycerate Mutants Reveals the Evolutionary Co-option of HOXD1 for Horn Patterning in Bovidae.

Mol Biol Evol 2021 Feb 2. Epub 2021 Feb 2.

CNRS UMR 7044-ARCHIMEDE-Misha, 67083 Strasbourg, France.

In the course of evolution, pecorans (i.e. higher ruminants) developed a remarkable diversity of osseous cranial appendages, collectively referred to as 'headgear', which likely share the same origin and genetic basis. However, the nature and function of the genetic determinants underlying their number and position remain elusive. Jacob and other rare populations of sheep and goats are characterized by polyceraty, the presence of more than two horns. Here, we characterize distinct POLYCERATE alleles in each species, both associated with defective HOXD1 function. We show that haploinsufficiency at this locus results in the splitting of horn bud primordia, likely following the abnormal extension of an initial morphogenetic field. These results highlight the key role played by this gene in headgear patterning and illustrate the evolutionary co-option of a gene involved in the early development of bilateria to properly fix the position and number of these distinctive organs of Bovidae.
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http://dx.doi.org/10.1093/molbev/msab021DOI Listing
February 2021

Evaluation of the Worldwide Occurrence of Rabies in Dogs and Cats Using a Simple and Homogenous Framework for Quantitative Risk Assessments of Rabies Reintroduction in Disease-Free Areas through Pet Movements.

Vet Sci 2020 Dec 18;7(4). Epub 2020 Dec 18.

USC EPIMAI, ANSES, Ecole Nationale Vétérinaire d'Alfort, F-94700 Maisons-Alfort, France.

Dog and cat rabies cases imported from rabies enzootic countries represent a major threat for areas that have acquired rabies-free status and quantitative risk analyses (QRAs) are developed in order to assess this risk of rabies reintroduction through dog and cat movements. Herein we describe a framework to evaluate dog and cat rabies incidence levels in exporting countries along with the associated uncertainty for such QRAs. For enzootic dog rabies areas (EDRAs), we extended and adapted a previously published method to specify the relationship between dog rabies vaccination coverage and canine rabies incidence; the relationship between dog and cat rabies incidences; and then to predict annual dog and cat rabies incidences. In non-enzootic dog rabies areas (nEDRAs), we provided annual incidence based on declared dog and cat rabies cases. For EDRAs, we predicted an annual incidence potentially greater than 1.5% in dogs and about ten times lower in cats with a high burden in Africa and Asia but much lower in Latin America. In nEDRAs, the occurrence of rabies was lower and of similar magnitude in dogs and cats. However, wildlife could still potentially infect dogs and cats through spillover events. This framework can directly be incorporated in QRAs of rabies reintroduction.
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http://dx.doi.org/10.3390/vetsci7040207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766548PMC
December 2020

Targeting the Respiratory Syncytial Virus N-P Complex with Constrained α-Helical Peptides in Cells and Mice.

Antimicrob Agents Chemother 2020 09 21;64(10). Epub 2020 Sep 21.

HES-SO Valais-Wallis, Institute of Life Technologies, Sion, Switzerland

Respiratory syncytial virus (RSV) is the main cause of severe respiratory infection in young children worldwide, and no therapies have been approved for the treatment of RSV infection. Data from recent clinical trials of fusion or L polymerase inhibitors for the treatment of RSV-infected patients revealed the emergence of escape mutants, highlighting the need for the discovery of inhibitors with novel mechanisms of action. Here we describe stapled peptides derived from the N terminus of the phosphoprotein (P) that act as replication inhibitors. We demonstrate that these peptides inhibit RSV replication and by preventing the formation of the N-P complex. The present strategy provides a novel means of targeting RSV replication with constrained macrocyclic peptides or small molecules and is broadly applicable to other viruses of the order.
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http://dx.doi.org/10.1128/AAC.00717-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508628PMC
September 2020

Chronic circadian disruption modulates breast cancer stemness and immune microenvironment to drive metastasis in mice.

Nat Commun 2020 06 24;11(1):3193. Epub 2020 Jun 24.

Inserm, U935, Université Paris Sud, Villejuif, France.

Breast cancer is the most common type of cancer worldwide and one of the major causes of cancer death in women. Epidemiological studies have established a link between night-shift work and increased cancer risk, suggesting that circadian disruption may play a role in carcinogenesis. Here, we aim to shed light on the effect of chronic jetlag (JL) on mammary tumour development. To do this, we use a mouse model of spontaneous mammary tumourigenesis and subject it to chronic circadian disruption. We observe that circadian disruption significantly increases cancer-cell dissemination and lung metastasis. It also enhances the stemness and tumour-initiating potential of tumour cells and creates an immunosuppressive shift in the tumour microenvironment. Finally, our results suggest that the use of a CXCR2 inhibitor could correct the effect of JL on cancer-cell dissemination and metastasis. Altogether, our data provide a conceptual framework to better understand and manage the effects of chronic circadian disruption on breast cancer progression.
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http://dx.doi.org/10.1038/s41467-020-16890-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314789PMC
June 2020

CLOUDED LEOPARD () MORBIDITY AND MORTALITY IN CAPTIVE-BRED POPULATIONS: A COMPREHENSIVE RETROSPECTIVE STUDY OF MEDICAL DATA FROM 271 INDIVIDUALS IN EUROPEAN, ASIAN, AND AUSTRALIAN ZOOS.

J Zoo Wildl Med 2020 Mar;51(1):150-158

Unité de recherche EpiMAI (USC Anses), 94700 Maisons-Alfort, France.

The clouded leopard () is classified as vulnerable on the International Union for the Conservation of Nature Red List of Threatened Species. However, diseases affecting this species across zoo populations are not well documented. The primary objective of this retrospective study was to identify common and significant causes of morbidity and mortality in captive-bred clouded leopards from European, Asian, and Australian institutions. Medical records from 44 zoological parks that held 271 clouded leopards from 1934 to 2017 were reviewed. Major causes of mortality in the dead leopards ( = 141) were respiratory disease (17%), maternal neglect and starvation (12%), generalized infectious disease (10%), digestive disease (10%), and trauma (10%). Six animals lived more than 20 yr and two were older than 22 yr. Diseases were recorded 344 times (average of two per leopard) in 166 living leopards. The body systems most frequently affected by disease in these 166 individuals were, in order of frequency, integumentary (prevalence = 21%), digestive (21%), respiratory (16%), musculoskeletal (12%), and urinary (10%) systems. Neoplasia (7%) was less frequent, followed by cardiovascular (5%), genital (3%), and viral (3%) disorders. Extensive, self-induced alopecia on the tail and dorsum was the most frequently reported dermatological disease, which is proposed to be called the "clouded leopard alopecia syndrome." The most common neoplasm was pheochromocytoma (1%), followed by squamous cell carcinoma of the paw pads, pleural mesothelioma and multicentric lymphomas (<1% each). Dilated cardiomyopathy (2%) was the most common cardiovascular disease. Bronchopneumonia (7%), enteritis (4%), and nephritis (4%) were the most frequently reported respiratory, digestive, and renal diseases, respectively. Diagnosed disease incidence was significantly higher in Europe. This paper reports the results of a comprehensive study of the causes of morbidity and mortality in European, Asian, and Australian clouded leopard zoo populations.
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http://dx.doi.org/10.1638/2019-0048DOI Listing
March 2020

Clinical cases of Bluetongue serotype 8 in calves in France in the 2018-2019 winter.

Transbound Emerg Dis 2020 May 8;67(3):1401-1405. Epub 2020 Jan 8.

Epidemiology Unit, Laboratory for Animal Health, ANSES, University Paris Est, Maisons-Alfort, France.

Bluetongue virus serotype 8 (BTV-8) caused an epizootic in Europe in 2006/09. Transplacental transmission of BTV-8 was demonstrated leading to abortions, congenital malformations or nervous clinical signs in newborn calves. BTV-8 re-emerged in France in 2015. Although the re-emergent strain is nearly genetically identical to the one that had circulated in 2006/2009, it has caused very few clinical cases. However, from mid-December 2018 to April 2019, cases of calves with congenital malformations or displaying nervous clinical signs occurred in some departments (French administrative unit) in mainland France. Blood samples from these animals were sent to local laboratories, and the positive ones were confirmed at the French Bluetongue reference laboratory (BT-NRL). Out of 580 samples found positive at the local laboratories, 544 were confirmed as RT-PCR BTV-8 positive. The 36 samples found positive in the local laboratories and negative in the BT-NRL were all at the limit of RT-PCR detection. Hundred eighty-eight of the confirmed samples were also tested for the presence of Schmallenberg virus (SBV) and bovine virus diarrhoea virus (BVDV) infection: 4 were found positive for BVDV and none for SBV. The main clinical signs recorded for 244 calves, for which a reporting form was completed by veterinarians, included nervous clinical signs (81%), amaurosis (72%) and decrease/ no suckling reflex (40%). Hydranencephaly and microphthalmia were reported in 19 calves out of 27 in which a necropsy was practiced after death or euthanasia. These results indicate that the re-emergent strain of BTV-8 can cross the transplacental barrier and cause congenital malformations or nervous clinical signs in calves.
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http://dx.doi.org/10.1111/tbed.13466DOI Listing
May 2020

Α de novo 3.8-Mb inversion affecting the EDA and XIST genes in a heterozygous female calf with generalized hypohidrotic ectodermal dysplasia.

BMC Genomics 2019 Sep 18;20(1):715. Epub 2019 Sep 18.

INRA, GABI, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France.

Background: In mammals, hypohidrotic ectodermal dysplasia (HED) is a genetic disorder that is characterized by sparse hair, tooth abnormalities, and defects in cutaneous glands. Only four genes, EDA, EDAR, EDARADD and WNT10A account for more than 90% of HED cases, and EDA, on chromosome X, is involved in 50% of the cases. In this study, we explored an isolated case of a female Holstein calf with symptoms similar to HED.

Results: Clinical examination confirmed the diagnosis. The affected female showed homogeneous hypotrichosis and oligodontia as previously observed in bovine EDAR homozygous and EDA hemizygous mutants. Under light microscopy, the hair follicles were thinner and located higher in the dermis of the frontal skin in the affected animal than in the control. Moreover, the affected animal showed a five-fold increase in the number of hair follicles and a four-fold decrease in the diameter of the pilary canals. Pedigree analysis revealed that the coefficient of inbreeding of the affected calf (4.58%) was not higher than the average population inbreeding coefficient (4.59%). This animal had ten ancestors in its paternal and maternal lineages. By estimating the number of affected cases that would be expected if any of these common ancestors carried a recessive mutation, we concluded that, if they existed, other cases of HED should have been reported in France, which is not the case. Therefore, we assumed that the causal mutation was dominant and de novo. By analyzing whole-genome sequencing data, we identified a large chromosomal inversion with breakpoints located in the first introns of the EDA and XIST genes. Genotyping by PCR-electrophoresis the case and its parents allowed us to demonstrate the de novo origin of this inversion. Finally, using various sources of information we present a body of evidence that supports the hypothesis that this mutation is responsible for a skewed inactivation of X, and that only the normal X can be inactivated.

Conclusions: In this article, we report a unique case of X-linked HED affected Holstein female calf with an assumed full inactivation of the normal X-chromosome, thus leading to a severe phenotype similar to that of hemizygous males.
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http://dx.doi.org/10.1186/s12864-019-6087-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749632PMC
September 2019

Newly identified LMO3-BORCS5 fusion oncogene in Ewing sarcoma at relapse is a driver of tumor progression.

Oncogene 2019 11 5;38(47):7200-7215. Epub 2019 Sep 5.

Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Université Paris-Sud 11, CNRS UMR 8203, Gustave Roussy Cancer Center, 94805, Villejuif, France.

Recently, we detected a new fusion transcript LMO3-BORCS5 in a patient with Ewing sarcoma within a cohort of relapsed pediatric cancers. LMO3-BORCS5 was as highly expressed as the characteristic fusion oncogene EWS/FLI1. However, the expression level of LMO3-BORCS5 at diagnosis was very low. Sanger sequencing depicted two LMO3-BORCS5 variants leading to loss of the functional domain LIM2 in LMO3 gene, and disruption of BORCS5. In vitro studies showed that LMO3-BORCS5 (i) increases proliferation, (ii) decreases expression of apoptosis-related genes and treatment sensitivity, and (iii) downregulates genes involved in differentiation and upregulates proliferative and extracellular matrix-related pathways. Remarkably, in vivo LMO3-BORCS5 demonstrated its high oncogenic potential by inducing tumors in mouse fibroblastic NIH-3T3 cell line. Moreover, BORCS5 probably acts, in vivo, as a tumor-suppressor gene. In conclusion, functional studies of fusion oncogenes at relapse are of great importance to define mechanisms involved in tumor progression and resistance to conventional treatments.
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http://dx.doi.org/10.1038/s41388-019-0914-3DOI Listing
November 2019

A First Step Toward Unraveling the Energy Metabolism in Endurance Horses: Comparison of Plasma Nuclear Magnetic Resonance Metabolomic Profiles Before and After Different Endurance Race Distances.

Front Mol Biosci 2019 12;6:45. Epub 2019 Jun 12.

Animal Genetics and Integrative Biology (GABI - UMR1313), INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France.

Endurance racing places high demands on energy metabolism pathways. Metabolomics can be used to investigate biochemical responses to endurance exercise in humans, laboratory animals, and horses. Although endurance horses have previously been assessed in the field (i.e., during races) using broad-window Nuclear Magnetic Resonance metabolomics, these studies included several different race locations, race distances, age classes, and race statuses (finisher or elimination). The present NMR metabolomics study focused on 40 endurance horses racing in three race categories over 90, 120, or 160 km. The three races took place in the same location. Given that energy metabolism is closely related to exercise intensity and duration (and therefore distance covered), the study's objective was to determine whether the metabolic pathways recruited during the race varied as a function of the total ride distance. For each horse, a plasma sample was collected the day before the race, and another was collected at the end of the race. Sixteen, 15, and 9 horses raced over 90, 120, and 160 km, respectively. Proton NMR spectra (500 MHz) were acquired for these 80 plasma samples. After processing, the spectra were divided into bins representing the NMR variables and then classified using orthogonal projection on latent structure models supervised by the sampling time (pre- or post-race) or the distance covered. The models revealed that the post-race metabolomic profiles are associated to the total ride distance groups. By combining biochemical assay results and NMR data in multiblock models, we further showed that enzymatic activities and metabolites are significantly associated to the race category. In the highest race category (160 km), there appears to be a metabolic switch from carbohydrate consumption to lipid consumption in order to maintain glycaemia. Furthermore, signs of protein breakdown were more apparent in the longest race category. The metabolic shift seen in the different racing categories could be related to a mixture of three important factors that are the ride distance, the training status and the inherited endurance capacity of the various horses competing.
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http://dx.doi.org/10.3389/fmolb.2019.00045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581711PMC
June 2019

Investigation of field intradermal tuberculosis test practices performed by veterinarians in France and factors that influence testing.

Res Vet Sci 2019 Jun 3;124:406-416. Epub 2019 May 3.

Research Unit in Epidemiology of Animal Infectious Diseases (EpiMAI USC Anses), Alfort National Veterinary School, 7, avenue du Général de Gaulle, 94704 Maisons-Alfort Cedex, France.

Bovine tuberculosis infection remains at a low but persistent level in French cattle herds and requires for its surveillance the use of tests with limited sensitivity and specificity. It thus appears essential to understand the reality of the field situation, to identify parameters which could affect how veterinarians perform these tests and how it can affect the sensitivity of the bovine tuberculosis surveillance system. We surveyed rural veterinarians (n = 1084), major stakeholders of the bovine tuberculosis surveillance system, after judgement (non-random) sampling to investigate their skin-test practices and their perception of the surveillance and control programs for this disease. The response rate was 19.4% (210/1084). The responses highlighted that veterinarians were aware of the importance of the fight against bovine tuberculosis and were resilient to the challenges and issues faced during fieldwork. However, we identified several areas of noncompliance with regulatory recommendations, particularly regarding the choice of injection site, verifying the quality of the injection, the method of test reading, and the reporting of non-negative test results. Multivariate analysis showed that veterinarians who had worked for fewer years in large-animal practice had better skin-test procedures. A higher proportion of performed comparative tests and a more positive perception of surveillance and control programs by veterinarians were associated with better skin-test practices. The areas of noncompliance identified in this study could be detrimental to the sensitivity of bovine tuberculosis surveillance but our results suggest that improving the information provided to veterinarians and increasing their awareness are feasible solutions to improve the surveillance efficacy.
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http://dx.doi.org/10.1016/j.rvsc.2019.05.001DOI Listing
June 2019

Multilayer intraclonal heterogeneity in chronic myelomonocytic leukemia.

Haematologica 2020 01 2;105(1):112-123. Epub 2019 May 2.

INSERM U1170, Gustave Roussy Cancer Center, Villejuif, France

The functional diversity of cells that compose myeloid malignancies, i.e., the respective roles of genetic and epigenetic heterogeneity in this diversity, remains poorly understood. This question is addressed in chronic myelomonocytic leukemia, a myeloid neoplasm in which clinical diversity contrasts with limited genetic heterogeneity. To generate induced pluripotent stem cell clones, we reprogrammed CD34 cells collected from a patient with a chronic myelomonocytic leukemia in which whole exome sequencing of peripheral blood monocyte DNA had identified 12 gene mutations, including a mutation in and two heterozygous mutations in in the founding clone and a secondary (G12D) mutation. CD34 cells from an age-matched healthy donor were also reprogrammed. We captured a part of the genetic heterogeneity observed in the patient, i.e. we analyzed five clones with two genetic backgrounds, without and with the (G12D) mutation. Hematopoietic differentiation of these clones recapitulated the main features of the patient's disease, including overproduction of granulomonocytes and dysmegakaryopoiesis. These analyses also disclosed significant discrepancies in the behavior of hematopoietic cells derived from induced pluripotent stem cell clones with similar genetic background, correlating with limited epigenetic changes. These analyses suggest that, beyond the coding mutations, several levels of intraclonal heterogeneity may participate in the yet unexplained clinical heterogeneity of the disease.
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http://dx.doi.org/10.3324/haematol.2018.208488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939510PMC
January 2020

Dynamic gene regulation by nuclear colony-stimulating factor 1 receptor in human monocytes and macrophages.

Nat Commun 2019 04 26;10(1):1935. Epub 2019 Apr 26.

INSERM U1170, Gustave Roussy Cancer Center, 94805, Villejuif, France.

Despite their location at the cell surface, several receptor tyrosine kinases (RTK) are also found in the nucleus, as either intracellular domains or full length proteins. However, their potential nuclear functions remain poorly understood. Here we find that a fraction of full length Colony Stimulating Factor-1 Receptor (CSF-1R), an RTK involved in monocyte/macrophage generation, migrates to the nucleus upon CSF-1 stimulation in human primary monocytes. Chromatin-immunoprecipitation identifies the preferential recruitment of CSF-1R to intergenic regions, where it co-localizes with H3K4me1 and interacts with the transcription factor EGR1. When monocytes are differentiated into macrophages with CSF-1, CSF-1R is redirected to transcription starting sites, colocalizes with H3K4me3, and interacts with ELK and YY1 transcription factors. CSF-1R expression and chromatin recruitment is modulated by small molecule CSF-1R inhibitors and altered in monocytes from chronic myelomonocytic leukemia patients. Unraveling this dynamic non-canonical CSF-1R function suggests new avenues to explore the poorly understood functions of this receptor and its ligands.
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http://dx.doi.org/10.1038/s41467-019-09970-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486619PMC
April 2019

Serpin B1 defect and increased apoptosis of neutrophils in Cohen syndrome neutropenia.

J Mol Med (Berl) 2019 05 7;97(5):633-645. Epub 2019 Mar 7.

Inserm UMR1170, Gustave Roussy Cancer Center, F-94800, Villejuif, France.

Cohen syndrome (CS) is a rare genetic disorder due to mutations in VPS13B gene. Among various clinical and biological features, CS patients suffer from inconsistent neutropenia, which is associated with recurrent but minor infections. We demonstrate here that this neutropenia results from an exaggerate rate of neutrophil apoptosis. Besides this increased cell death, which occurs in the absence of any endoplasmic reticulum stress or defect in neutrophil elastase (ELANE) expression or localization, all neutrophil functions appeared to be normal. We showed a disorganization of the Golgi apparatus in CS neutrophils precursors, that correlates with an altered glycosylation of ICAM-1 in these cells, as evidenced by a migration shift of the protein. Furthermore, a striking decrease in the expression of SERPINB1 gene, which encodes a critical component of neutrophil survival, was detected in CS neutrophils. These abnormalities may account for the excessive apoptosis of neutrophils leading to neutropenia in CS. KEY MESSAGES: Cohen syndrome patients' neutrophils display normal morphology and functions. Cohen syndrome patients' neutrophils have an increased rate of spontaneous apoptosis compared to healthy donors' neutrophils. No ER stress or defective ELA2 expression or glycosylation was observed in Cohen syndrome patients' neutrophils. SerpinB1 expression is significantly decreased in Cohen syndrome neutrophils as well as in VPS13B-deficient cells.
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http://dx.doi.org/10.1007/s00109-019-01754-4DOI Listing
May 2019

A miR-150/TET3 pathway regulates the generation of mouse and human non-classical monocyte subset.

Nat Commun 2018 12 21;9(1):5455. Epub 2018 Dec 21.

INSERM U1170, Gustave Roussy Cancer Center, 94805, Villejuif, France.

Non-classical monocyte subsets may derive from classical monocyte differentiation and the proportion of each subset is tightly controlled. Deregulation of this repartition is observed in diverse human diseases, including chronic myelomonocytic leukemia (CMML) in which non-classical monocyte numbers are significantly decreased relative to healthy controls. Here, we identify a down-regulation of hsa-miR-150 through methylation of a lineage-specific promoter in CMML monocytes. Mir150 knock-out mice demonstrate a cell-autonomous defect in non-classical monocytes. Our pulldown experiments point to Ten-Eleven-Translocation-3 (TET3) mRNA as a hsa-miR-150 target in classical human monocytes. We show that Tet3 knockout mice generate an increased number of non-classical monocytes. Our results identify the miR-150/TET3 axis as being involved in the generation of non-classical monocytes.
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http://dx.doi.org/10.1038/s41467-018-07801-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303340PMC
December 2018

Efficacy and Tolerability of Atypical Antipsychotics in the Treatment of Delirium: A Systematic Review of the Literature.

Psychosomatics 2019 Jan - Feb;60(1):18-26. Epub 2018 May 31.

Department of Psychiatry, Antwerp University Hospital (UZA), Antwerp, Belgium.; Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine and Health Sciences, University of Antwerp (UA), Antwerp, Belgium. Electronic address:

Background: Although haloperidol is the most widely used drug in the treatment of delirium, evidence on the relevance of atypical antipsychotics (AAPs) is growing.

Objective: To review the literature on the efficacy and tolerability of AAPs in the treatment of delirium.

Methods: A systematic search of the literature published before April 2018 was performed on PubMed using the following search strings: "Delirium" and "Atypical antipsychotics", "Novel antipsychotics", "New antipsychotics", "Quetiapine", "Olanzapine", "Aripiprazole", "Risperidone", "Paliperidone", "Clozapine", "Asenapine", "Iloperidone", "Amisulpiride", "Ziprasidone", "Zotepine", "Sertindole", "Lurasidone" or "Perospirone".

Results: Twelve randomized controlled trials (RCTs) and 22 open trials were considered. Despite an overall lack of large-scale RCTs, there is some evidence supporting the efficacy of olanzapine and quetiapine in placebo controlled trials. In a recent and large RCT in elderly patients, risperidone and/or haloperidol were associated with a significantly worse outcome than placebo. While preliminary, the current comparative studies suggest that haloperidol and the AAPs olanzapine, quetiapine and risperidone are similarly effective, although treatment with AAPs is associated with a reduced incidence of extrapyramidal symptoms. Ziprasidone was not shown to be effective. No RCTs are available for other AAPs.

Conclusions: Although the current evidence of the efficacy and tolerability of AAPs in the treatment of delirium is limited and the heterogeneity of the data precluded a meta-analysis, olanzapine and quetiapine seem to be adequate alternatives to haloperidol, especially in patients who are vulnerable for extrapyramidal symptoms, who require sedation or who have a history of haloperidol intolerance. Evidently, larger-scale RCTs are urgently required.
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http://dx.doi.org/10.1016/j.psym.2018.05.011DOI Listing
August 2019

Overview of foot-and-mouth disease awareness among farmers and veterinarians in France.

Vet Rec 2018 08 15;183(5):161. Epub 2018 Jun 15.

Epidemiology Unit, Laboratory for Animal Health, University Paris Est, Anses, Maisons-Alfort, France.

Foot-and-mouth disease (FMD) is of major concern in most countries including Europe, where no outbreaks have occurred since a decade. Indeed, the risk of FMD introduction from infected countries is not negligible and the awareness of field stakeholders (farmers, veterinarians) is essential to ensure an effective detection of the viral circulation. The French veterinary services launched in 2015 a survey to estimate the awareness of farmers and veterinarians and their knowledge about epidemiological and regulatory aspects of FMD. Official health visits were used to collect information from cattle farmers and veterinarians through two separate questionnaires. The results show that not all cattle farmers were aware of the risk of FMD reintroduction in France and of its routes of infection and speed of dissemination. As for the veterinarians, their promptness to report a suspicion was dependent on the occurrence of FMD cases in European countries. These results highlight key aspectsregarding FMD epidemiology which should be regularly reminded to the field stakeholders in FMD-free countries to increase their awareness and thus ensure an effective early detection in case of FMD introduction.
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http://dx.doi.org/10.1136/vr.104733DOI Listing
August 2018

Effects of induced rumination on body dissatisfaction: Is there any difference between men and women?

J Behav Ther Exp Psychiatry 2018 12 19;61:1-6. Epub 2018 May 19.

Univ. Lille, EA 4072 - PSITEC - Psychologie: Interactions Temps Émotions Cognition, F-59000 Lille, France. Electronic address:

Background And Objectives: Rumination is a factor in the development and maintenance of body dissatisfaction. However, no study has yet investigated the impact of the type of rumination on body image. The first aim of this study was to examine whether the induction of analytic-abstract vs. concrete-experiential rumination affects body dissatisfaction following an induction of negative body image. The second objective was to examine gender differences in these effects.

Methods: Following induction of negative body image, 102 university undergraduates were randomly assigned to one of three experimental conditions-distraction, concrete rumination or abstract rumination.

Results: As expected, there were significant main effects of gender and condition, and a significant interaction between gender and condition on change in body dissatisfaction. In women abstract rumination predicted the highest increase in body dissatisfaction, whereas concrete rumination predicted the highest increase in body dissatisfaction in men.

Limitations: Given that our sample consisted of undergraduate students, our findings cannot be generalized to clinical sample suffering from eating disorder.

Conclusions: The different types of rumination seem to impact differentially body dissatisfaction in men and women.
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http://dx.doi.org/10.1016/j.jbtep.2018.05.005DOI Listing
December 2018

Perceptions and acceptability of some stakeholders about the bovine tuberculosis surveillance system for wildlife (Sylvatub) in France.

PLoS One 2018 15;13(3):e0194447. Epub 2018 Mar 15.

USC EPIMAI Unit, Anses, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France.

Bovine tuberculosis (bTB) is a common disease of cattle and wildlife, with economic repercussions and implications for animal and human health. The surveillance of bTB in wildlife is particularly important, to shed light on the epidemiological role of wild species and for the adaptation of control measures. In France, a bTB surveillance system for free-ranging wildlife, the Sylvatub system, was launched in 2011 on wild boars, red deer, roe deer and badgers. It relies on active and passive surveillance activities, constrained by practical difficulties, such as the accessibility of wild animals, and regulatory rules for the trapping of badgers, for example. We report here the first assessment of stakeholders' perceptions of the Sylvatub system and its acceptability, based on 20 individual semi-structured interviews with three types of stakeholder (collectors, coordinators, officers) in areas with different rates of bTB infection. With the caveat that these findings cannot be assumed to be representative of the national situation, we found that the Sylvatub system was considered useful by all the stakeholders interviewed. Those from the world of hunting participate in surveillance mostly to help livestock farmers, who are not systematically involved in bTB surveillance in wildlife. Many practical and regulatory constraints were raised, which could be offset by recognition of the work done by the "hunting community", to maintain the willingness of these individuals to participate. We also identified a need for improvements in communication and information. Qualitative information, such as that collected here, is essential to improve our understanding of the reasons favoring and disfavoring participation in surveillance, and should be taken into account in the evaluation process. These results are relevant to hunters and to veterinary authorities wishing to identify the determinants of participation in the Sylvatub system. They could provide support for decision-making processes to improve surveillance strategies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0194447PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854387PMC
July 2018

Gene transfer into hematopoietic stem cells reduces HLH manifestations in a murine model of Munc13-4 deficiency.

Blood Adv 2017 Dec 21;1(27):2781-2789. Epub 2017 Dec 21.

Human Lymphohaematopoiesis Laboratory, INSERM U1163, Paris, France.

Patients with mutations in the gene (coding for Munc13-4 protein) suffer from familial hemophagocytic lymphohistiocytosis type 3 (FHL3), a life-threatening immune and hyperinflammatory disorder. The only curative treatment is allogeneic hematopoietic stem cell (HSC) transplantation, although the posttreatment survival rate is not satisfactory. Here, we demonstrate the curative potential of gene correction of HSCs in a murine model of FHL3. We generated a self-inactivating lentiviral vector, used it to complement HSCs from -deficient (Jinx) mice, and transplanted the cells back into the irradiated Jinx recipients. This procedure led to complete reconstitution of the immune system (ie, to wild-type levels). The recipients were then challenged with lymphocytic choriomeningitis virus to induce hemophagocytic lymphohistiocytosis (HLH)-like manifestations. All the clinical and biological signs of HLH were significantly reduced in mice having undergone HSC gene correction than in nontreated animals. This beneficial effect was evidenced by the correction of blood cytopenia, body weight gain, normalization of the body temperature, decreased serum interferon-γ level, recovery of liver damage, and decreased viral load. These improvements can be explained by the restoration of the CD8 T lymphocytes' cytotoxic function (as demonstrated here in an in vitro degranulation assay). Overall, our results demonstrate the efficacy of HSC gene therapy in an FHL-like setting of immune dysregulation.
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http://dx.doi.org/10.1182/bloodadvances.2017012088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745141PMC
December 2017

First prenatal diagnosis of a 'pure' 9q34.3 deletion (Kleefstra syndrome): A case report and literature review.

J Obstet Gynaecol Res 2018 Mar 21;44(3):570-575. Epub 2017 Nov 21.

EA7404-GIG, University Simone Veil of Health Sciences, UVSQ, Montigny le Bretonneux, France.

Kleefstra syndrome (KS) is characterized by developmental delay, intellectual disability, hypotonia and distinct facial features. Additional clinical features include congenital heart defects, cerebral abnormalities, urogenital defects and weight gain. The syndrome is caused by a microdeletion in chromosomal region 9q34.3 (in 85% of cases) or by a mutation in the EHMT1 gene coding for euchromatin histone methyltransferase 1. The prenatal phenotype has not yet been characterized. Herein, we sought to define this phenotype on the basis of a new case report and literature review.
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http://dx.doi.org/10.1111/jog.13517DOI Listing
March 2018

Gallein, a Gβγ subunit signalling inhibitor, inhibits metastatic spread of tumour cells expressing OR51E2 and exposed to its odorant ligand.

BMC Res Notes 2017 Oct 30;10(1):541. Epub 2017 Oct 30.

Vectorologie et Thérapeutiques Anti-cancéreuses, UMR8203, CNRS, Univ. Paris-Sud, Université Paris-Saclay, Gustave Roussy, Villejuif, France.

Objective: We previously reported that the olfactory receptor OR51E2, overexpressed in LNCaP prostate cancer cells, promotes cell invasiveness upon stimulation of its agonist β-ionone, and this phenomenon increases metastatic spread. Furthermore, we showed that the induced cell invasiveness involves a PI3 kinase dependent signalling pathway. We report here the results of a new investigation to address whether gallein, a small inhibitor of G protein βγ subunit interaction with PI3 kinase, can inhibit β-ionone effects both in vitro and in vivo.

Results: We demonstrate that gallein can inhibit the β-ionone-induced cell invasiveness in vitro, as well as the spread of metastases in vivo. LNCaP cell invasiveness, assessed using spheroid cultures in collagen gels in vitro, was increased by β-ionone and the effect was reversed by co-administration of gallein. LNCaP tumour cells, subcutaneously inoculated to immunodeficient mice, generated more metastases in vivo when β-ionone was applied through the skin. Furthermore, the intraperitoneal injection of gallein inhibited this increased metastasis spread. Our results thus support the role of OR51E2 in the β-ionone observed effects, and suggest that gallein could be a potential new agent in personalized medicine of the tumours expressing OR51E2.
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http://dx.doi.org/10.1186/s13104-017-2879-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663063PMC
October 2017

Cost-effectiveness evaluation of bovine tuberculosis surveillance in wildlife in France (Sylvatub system) using scenario trees.

PLoS One 2017 11;12(8):e0183126. Epub 2017 Aug 11.

Ecole vétérinaire d'Alfort (Alfort National Veterinary School), Research unit EpiMAI USC Anses (Epidemiology of Animal Infectious Disease), Université Paris Est, Maisons-Alfort, France.

Bovine tuberculosis (bTB) is a common disease in cattle and wildlife, with health, zoonotic and economic implications. Infected wild animals, and particularly reservoirs, could hinder eradication of bTB from cattle populations, which could have an important impact on international cattle trade. Therefore, surveillance of bTB in wildlife is of particular importance to better understand the epidemiological role of wild species and to adapt the control measures. In France, a bTB surveillance system for free-ranging wildlife, the Sylvatub system, has been implemented since 2011. It relies on three surveillance components (SSCs) (passive surveillance on hunted animals (EC-SSC), passive surveillance on dead or dying animals (SAGIR-SSC) and active surveillance (PSURV-SSC)). The effectiveness of the Sylvatub system was previously assessed, through the estimation of its sensitivity (i.e. the probability of detecting at least one case of bTB infection by each SSC, specie and risk-level area). However, to globally assess the performance of a surveillance system, the measure of its sensitivity is not sufficient, as other factors such as economic or socio-economic factors could influence the effectiveness. We report here an estimation of the costs of the surveillance activities of the Sylvatub system, and of the cost-effectiveness of each surveillance component, by specie and risk-level, based on scenario tree modelling with the same tree structure as used for the sensitivity evaluation. The cost-effectiveness of the Sylvatub surveillance is better in higher-risk departments, due in particular to the higher probability of detecting the infection (sensitivity). Moreover, EC-SSC, which has the highest unit cost, is more efficient than the surveillance enhanced by the SAGIR-SSC, due to its better sensitivity. The calculation of the cost-effectiveness ratio shows that PSURV-SSC remains the most cost-effective surveillance component of the Sylvatub system, despite its high cost in terms of coordination, sample collection and laboratory analysis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183126PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553909PMC
October 2017

The Effects of Weaning Methods on Gut Microbiota Composition and Horse Physiology.

Front Physiol 2017 25;8:535. Epub 2017 Jul 25.

PRC, Institut National de la Recherche Agronomique, Centre National de la Recherche Scientifique, IFCE, Université de ToursNouzilly, France.

Weaning has been described as one of the most stressful events in the life of horses. Given the importance of the interaction between the gut-brain axis and gut microbiota under stress, we evaluated (i) the effect of two different weaning methods on the composition of gut microbiota across time and (ii) how the shifts of gut microbiota composition after weaning affect the host. A total of 34 foals were randomly subjected to a progressive (P) or an abrupt (A) weaning method. In the P method, mares were separated from foals at progressively increasing intervals every day, starting from five min during the fourth week prior to weaning and ending with 6 h during the last week before weaning. In the A method, mares and foals were never separated prior to weaning (0 d). Different host phenotypes and gut microbiota composition were studied across 6 age strata (days -30, 0, 3, 5, 7, and 30 after weaning) by 16S rRNA gene sequencing. Results revealed that the beneficial species belonging to , and were more abundant in the A group prior to weaning compared to the P group, suggesting that the gut microbiota in the A cohort was better adapted to weaning. , on the other hand, showed the opposite pattern after weaning. Fungal loads, which are thought to increase the capacity for fermenting the complex polysaccharides from diet, were higher in P relative to A. Beyond the effects of weaning methods, maternal separation at weaning markedly shifted the composition of the gut microbiota in all foals, which fell into three distinct community types at 3 days post-weaning. Most genera in community type 2 (i.e., XI, and spp.) were negatively correlated with salivary cortisol levels, but positively correlated with telomere length and N-butyrate production. Average daily gain was also greater in the foals harboring a community type 2 microbiota. Therefore, community type 2 is likely to confer better stress response adaptation following weaning. This study identified potential microbial biomarkers that could predict the likelihood for physiological adaptations to weaning in horses, although causality remains to be addressed.
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http://dx.doi.org/10.3389/fphys.2017.00535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524898PMC
July 2017

Endurance Exercise Ability in the Horse: A Trait with Complex Polygenic Determinism.

Front Genet 2017 28;8:89. Epub 2017 Jun 28.

Institut National de la Recherche Agronomique, AgroParisTech, Université Paris Saclay, Département Sciences du Vivant, UMR 1313 Génétique Animale et Biologie IntégrativeJouy-en-Josas, France.

Endurance horses are able to run at more than 20 km/h for 160 km (in bouts of 30-40 km). This level of performance is based on intense aerobic metabolism, effective body heat dissipation and the ability to endure painful exercise. The known heritabilities of endurance performance and exercise-related physiological traits in Arabian horses suggest that adaptation to extreme endurance exercise is influenced by genetic factors. The objective of the present genome-wide association study (GWAS) was to identify single nucleotide polymorphisms (SNPs) related to endurance racing performance in 597 Arabian horses. The performance traits studied were the total race distance, average race speed and finishing status (qualified, eliminated or retired). We used three mixed models that included a fixed allele or genotype effect and a random, polygenic effect. Quantile-quantile plots were acceptable, and the regression coefficients for actual vs. expected log-values ranged from 0.865 to 1.055. The GWAS revealed five significant quantitative trait loci (QTL) corresponding to 6 SNPs on chromosomes 6, 1, 7, 16, and 29 (two SNPs) with corrected -values from 1.7 × 10 to 1.8 × 10. Annotation of these 5 QTL revealed two genes: sortilin-related VPS10-domain-containing receptor 3 () on chromosome 1 is involved in protein trafficking, and solute carrier family 39 member 12 () on chromosome 29 is active in zinc transport and cell homeostasis. These two coding genes could be involved in neuronal tissues (CNS). The other QTL on chromosomes 6, 7, and 16 may be involved in the regulation of the gene expression through non-coding RNAs, CpG islands and transcription factor binding sites. On chromosome 6, a new candidate equine long non-coding RNA ( ortholog: opposite antisense transcript 1 of potassium voltage-gated channel subfamily Q member 1 gene) was predicted and validated by RT-qPCR in primary cultures of equine myoblasts and fibroblasts. This lncRNA could be one element of the cardiac rhythm regulation. Our GWAS revealed that equine performance during endurance races is a complex polygenic trait, and is partially governed by at least 5 QTL: two coding genes involved in neuronal tissues and three other loci with many regulatory functions such as slowing down heart rate.
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http://dx.doi.org/10.3389/fgene.2017.00089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5488500PMC
June 2017

ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia.

Cancer Cell 2017 03;31(3):452-465

INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, 39 rue Camille Desmoulins, 94800 Villejuif, France; Gustave Roussy, 94800 Villejuif, France; Université Paris Diderot, 75013 Paris, France; Université Paris-Sud, 91405 Orsay, France. Electronic address:

Chimeric transcription factors are a hallmark of human leukemia, but the molecular mechanisms by which they block differentiation and promote aberrant self-renewal remain unclear. Here, we demonstrate that the ETO2-GLIS2 fusion oncoprotein, which is found in aggressive acute megakaryoblastic leukemia, confers megakaryocytic identity via the GLIS2 moiety while both ETO2 and GLIS2 domains are required to drive increased self-renewal properties. ETO2-GLIS2 directly binds DNA to control transcription of associated genes by upregulation of expression and interaction with the ETS-related ERG protein at enhancer elements. Importantly, specific interference with ETO2-GLIS2 oligomerization reverses the transcriptional activation at enhancers and promotes megakaryocytic differentiation, providing a relevant interface to target in this poor-prognosis pediatric leukemia.
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http://dx.doi.org/10.1016/j.ccell.2017.02.006DOI Listing
March 2017