Navarro J.-M.,Aix - Marseille University |
Navarro J.-M.,French Institute of Health and Medical Research |
Navarro J.-M.,French National Center for Scientific Research |
Touzart A.,University of Paris Descartes |
And 51 more authors.
Nature Communications | Year: 2015
T-cell acute lymphoblastic leukaemias (T-ALL) are aggressive malignant proliferations characterized by high relapse rates and great genetic heterogeneity. TAL1 is amongst the most frequently deregulated oncogenes. Yet, over half of the TAL1 + cases lack TAL1 lesions, suggesting unrecognized (epi)genetic deregulation mechanisms. Here we show that TAL1 is normally silenced in the T-cell lineage, and that the polycomb H3K27me3-repressive mark is focally diminished in TAL1 + T-ALLs. Sequencing reveals that >20% of monoallelic TAL1 + patients without previously known alterations display microinsertions or RAG1/2-mediated episomal reintegration in a single site 5″ to TAL1. Using 'allelic-ChIP' and CrispR assays, we demonstrate that such insertions induce a selective switch from H3K27me3 to H3K27ac at the inserted but not the germline allele. We also show that, despite a considerable mechanistic diversity, the mode of oncogenic TAL1 activation, rather than expression levels, impact on clinical outcome. Altogether, these studies establish site-specific epigenetic desilencing as a mechanism of oncogenic activation. © 2015 Macmillan Publishers Limited. All rights reserved.
PubMed | Laboratoire Hematologie, Aix - Marseille University, University of Paris Descartes, AP HP Hopital St Louis and 2 more.
Type: | Journal: Nature communications | Year: 2015
T-cell acute lymphoblastic leukaemias (T-ALL) are aggressive malignant proliferations characterized by high relapse rates and great genetic heterogeneity. TAL1 is amongst the most frequently deregulated oncogenes. Yet, over half of the TAL1(+) cases lack TAL1 lesions, suggesting unrecognized (epi)genetic deregulation mechanisms. Here we show that TAL1 is normally silenced in the T-cell lineage, and that the polycomb H3K27me3-repressive mark is focally diminished in TAL1(+) T-ALLs. Sequencing reveals that >20% of monoallelic TAL1(+) patients without previously known alterations display microinsertions or RAG1/2-mediated episomal reintegration in a single site 5 to TAL1. Using allelic-ChIP and CrispR assays, we demonstrate that such insertions induce a selective switch from H3K27me3 to H3K27ac at the inserted but not the germline allele. We also show that, despite a considerable mechanistic diversity, the mode of oncogenic TAL1 activation, rather than expression levels, impact on clinical outcome. Altogether, these studies establish site-specific epigenetic desilencing as a mechanism of oncogenic activation.
Aanei C.M.,Laboratoire Hematologie |
Aanei C.M.,Grigore T. Popa University of Medicine and Pharmacy |
Eloae F.Z.,Grigore T. Popa University of Medicine and Pharmacy |
Flandrin-Gresta P.,Laboratoire Hematologie |
And 8 more authors.
Experimental Cell Research | Year: 2011
Direct cell-cell contact between haematopoietic progenitor cells (HPCs) and their cellular microenvironment is essential to maintain "stemness". In cancer biology, focal adhesion (FA) proteins are involved in survival signal transduction in a wide variety of human tumours. To define the role of FA proteins in the haematopoietic microenvironment of myelodysplastic syndromes (MDS), CD73-positive mesenchymal stromal cells (MSCs) were immunostained for paxillin, pFAK [Y 397], and HSP90α/β and p130CAS, and analysed for reactivity, intensity and cellular localisation. Immunofluorescence microscopy allowed us to identify qualitative and quantitative differences, and subcellular localisation analysis revealed that in pathological MSCs, paxillin, pFAK [Y 397], and HSP90α/β formed nuclear molecular complexes. Increased expression of paxillin, pFAK [Y 397], and HSP90α/β and enhanced nuclear co-localisation of these proteins correlated with a consistent proliferative advantage in MSCs from patients with refractory anaemia with excess blasts (RAEB) and negatively impacted clonogenicity of HPCs. These results suggest that signalling via FA proteins could be implicated in HPC-MSC interactions. Further, because FAK is an HSP90α/β client protein, these results suggest the utility of HSP90α/β inhibition as a target for adjuvant therapy for myelodysplasia. © 2011 Elsevier Inc.
Modalities for preparation, cryopreservation, thawing of hematopoietic stem cells and precautions for infusion to patient: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)
PubMed | Laboratoire Of Therapie Cellulaire, CHU Sart Tilman, Institute Paoli Calmettes, Nancy University Hospital Center and 8 more.
Type: Journal Article | Journal: Bulletin du cancer | Year: 2016
To date, despite an existing regulatory framework and standards, there are no true technical recommendations. A survey of 23cell processing facilities (France, Belgium and Switzerland) has allowed to overview current practices according to cellular products specifications upon arrival at the facility, with modalities for their preparation prior to cryopreservation, storage, thawing and finally for infusion to patient. Data analysis shows great variability of collected volumes and cell concentrations in cellular products. Despite homogeneous practices for handling cells at the facility, methods vary between centers, especially for the choice of cryoprotective solutions and thawing methods. During the workshop, practices have been discussed and summarized to write of recommendations about the following topics: processing and cryopreservation, thawing, bedside precautions (for infusion). This work identifies some improvements in terms of collection, choice of wash solution of thawed cells and validation of the conditions of carriage.
Loosveld M.,Aix - Marseille University |
Loosveld M.,French Institute of Health and Medical Research |
Loosveld M.,French National Center for Scientific Research |
Loosveld M.,Laboratoire Hematologie |
And 18 more authors.
Oncotarget | Year: 2014
T-ALL patients treated with intensive chemotherapy achieve high rates of remission. However, frequent long-term toxicities and relapses into chemotherapy-refractory tumors constitute major clinical challenges which could be met by targeted therapies. c-MYC is a central oncogene in T-ALL, prompting the exploration of the efficacy of MYC inhibitors such as JQ1 (BET-bromodomain inhibitor), and SAHA (HDAC inhibitor). Using a standardized ex vivo drug screening assay, we show here that JQ1 and SAHA show competitive efficiency compared to inhibitors of proteasome, PI3K/AKT/mTOR and NOTCH pathways, and synergize in combination with Vincristine. We also compared for the first time the in vivo relevance of such associations in mice xenografted with human primary T-ALLs. Our data indicate that although treatments combining JQ1 or SAHA with chemotherapeutic regimens might represent promising developments in T-ALL, combinations will need to be tailored to specific subgroups of responsive patients, the profiles of which still remain to be precisely defined. © 2008-2014 Impact Journals, LLC.
Virard F.,University of Lyon |
Cousty S.,University Paul Sabatier |
Cousty S.,Toulouse University Hospital Center |
Cambus J.-P.,Toulouse University Hospital Center |
And 7 more authors.
PLoS ONE | Year: 2015
Introduction: Cold plasma is a partially ionized gas generated by an electric field at atmospheric pressure that was initially used in medicine for decontamination and sterilization of inert surfaces. There is currently growing interest in using cold plasma for more direct medical applications, mainly due to the possibility of tuning it to obtain selective biological effects in absence of toxicity for surrounding normal tissues. While the therapeutic potential of cold plasma in chronic wound, blood coagulation, and cancer treatment is beginning to be documented, information on plasma/cell interaction is so far limited and controversial. Methods and Results: Using normal primary human fibroblast cultures isolated from oral tissue, we sought to decipher the effects on cell behavior of a proprietary cold plasma device generating guided ionization waves carried by helium. In this model, cold plasma treatment induces a predominantly necrotic cell death. Interestingly, death is not triggered by a direct interaction of the cold plasma with cells, but rather via a transient modification in the microenvironment. We show that modification of the microenvironment redox status suppresses treatment toxicity and protects cells from death. Moreover, necrosis is not accidental and seems to be an active response to an environmental cue, as its execution can be inhibited to rescue cells. Conclusion: These observations will need to be taken into account when studying in vitro plasma/cell interaction and may have implications for the design and future evaluation of the efficacy and safety of this new treatment strategy. © 2015 Virard et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Neonatal renal vein thrombosis in a heterozygous carrier of both factor V Leiden and the MTHFR gene mutation [Thrombose néonatale de la veine rénale et double hétérozygotie pour la mutation du facteur V de Leiden et du gène de la MTHFR]
Wannes S.,Service pediatrie |
Soua H.,Service pediatrie |
Ghanmi S.,Service pediatrie |
Braham H.,Service des laboratoires |
And 4 more authors.
Archives de Pediatrie | Year: 2012
Renal vein thrombosis (RVT) is a rare but potentially serious neonatal disease. Its epidemiology and its clinical and biological expression are currently well known, but its etiological exploration, like that of venous thromboembolism, is increasingly complex. Perinatal risk factors such as prematurity, dehydration, and birth asphyxia have lost their direct accountability at the expense of their interaction with constitutional disorders of hemostasis. We report a case of RVT in a newborn who was a heterozygous carrier of both factor V Leiden and the methylene tetrahydrofolate reductase (MTHFR) gene mutation. We recall the clinical and epidemiological characteristics. A search for inborn blood coagulation disorders should be systematic in the newborn infant with venous thrombosis because of the risk of recurrence, taking into account perinatal factors and maternal thrombophilia (especially if RVT is established during the prenatal period). © 2012 Elsevier Masson SAS.