Mécanismes d’oncogenèse dans les Leucémies Aiguës Lymphoblastiques T : TAL1, MYC et ciblage thérapeutique

La leucémie aiguë lymphoblastique T (LAL-T) est une hémopathie maligne représentant environ 15% des LAL pédiatriques et 25% des LAL de l'adulte. Malgré l'amélioration de la prise en charge des LAL, le devenir des patients atteints de LAL-T reste péjoratif avec environ 30% de rechute dans les deux années suivant le diagnostic. En effet, les LAL-T constituent un groupe de leucémies particulièrement hétérogène dans lequel différents oncogènes sont activés dans des combinaisons diverses. De ce fait, l'identification de voies oncogéniques pouvant être ciblées thérapeutiquement reste un des défis majeurs dans la recherche translationnelle des LAL-T. Au cours de ma thèse, je me suis intéressée au mode d'activation de deux oncogènes majeurs dans les LAL-T: les oncogènes MYC et TAL1. Nous avons montré que l'hyperactivation de la voie AKT, notamment à travers les mutations perte de fonction du gène PTEN induisait une augmentation de la protéine MYC. Nos résultats suggèrent que les axes MYC et PTEN/AKT pourraient représenter des cibles thérapeutiques potentielles dans les LAL-T. Nous avons alors conduit une étude pharmacologique révélant qu'in vitro plusieurs drogues induisent l'apoptose ou l'arrêt de prolifération des cellules de LAL-T. Par ailleurs, certaines de ces drogues sont responsables d'une inhibition de l'expression de MYC. L'efficacité de ces drogues est maintenant testée in vivo grâce à des souris immunodéficientes xénogreffées avec des cellules de LAL-T primaires humaines.T-Cell Acute Lymphoblastic Leukemia (T-ALL) are malignant proliferations of thymocytes which represents around 15% of pediatric and 25% of adult ALL. Despite indisputable therapeutic progress, T-ALL remains of poor prognosis and about 30% of cases relapse within the first 2 years following diagnosis. In fact T-ALL is a heterogeneous disease in which different oncogenes are activated in various combinations and this represents a major hurdle in the molecular analysis of T-ALL oncogenesis. During my thesis I investigated how MYC and TAL1, two key oncogenes in T-ALL, are activated. We showed that hyperactivation of AKT pathway, notably through PTEN loss-of-function mutations, gives rise to an increase of MYC protein level. Our data suggest that in T-ALL, MYC and PTEN/AKT axis may represent potential therapeutic targets. Then, we performed a pharmacological study which shows that, in vitro, several drugs lead to apoptosis or proliferation arrest of T-ALL cells. Moreover, some of those drugs impede MYC expression. The efficacy of these compounds are now tested in vivo using immunodeficient mice engrafted with primary human T-ALL blasts

Congélation du cortex ovarien en vue de la préservation de la fertilité chez la petite fille et la jeune femme (état des lieux, revue de la littérature, bilan de l'expérience au CHU de Nantes)

Les récents progrès des traitements anti-cancéreux ont permis l'amélioration de la survie des patientes. Chez ces patientes survivantes de cancer, se pose désormais le problème de la qualité de vie après la maladie. Or, ces traitements anti-cancéreux sont souvent responsables d une insuffisance ovarienne précoce. La cryopréservation du tissu ovarien est une voie de recherche pour restaurer la fertilité des patientes après guérison. L annonce récente de deux naissances dans l espèce humaine suite à une cryopréservation et greffe ovarienne a été porteuse de beaucoup d espoir. Notre étude s est intéressée aux cas d autoconservations de tissu ovarien réalisés dans le service de médecine et de biologie de la reproduction du CHU de Nantes entre 1995 et 2007 afin d évaluer si la cryopréservation ovarienne était réalisée au meilleur moment. D après nos résultats, nous pensons qu il serait préférable de réaliser le prélèvement de tissu ovarien avant la mise en place du traitement par chimiothérapie, cela bien sûr dans les limites possibles de l urgence thérapeutique.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Detection of unstable haemoglobin variants with Sysmex XN‐10

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Contents and Structural Features of Water-Extractable Arabinogalactan in Wheat Flour Fractions

In Camp Remy Buhler MLU-202 roller mill flour fractions, the levels of water-extractable arabinoxylan (WE-AX) (0.30-0.41%, dry basis) were comparable to those of water-extractable arabinogalactan (WE-AG) (0.29-0.38%, dry basis). Minaret had more WE-AX (0.49-0.68%, dry basis) than WE-AG (0.27-0.36%, dry basis). The ratio of WE-AG to WE-AX for the different flour fractions varied between 0.83 and 1.03 for Camp Remy and between 0.46 and 0.57 for Minaret. For both wheat varieties, the percentage of WE-AX and WE-AG was higher for the second and third reduction roll fractions than for the three break and the first reduction roll fractions. There was little structural variation in WE-AG of different flour fractions. The arabinose to galactose (A/G) ratio (w/w) varied between 0.63 and 0.69 for Camp Remy WE-AG and between 0.66 and 0.72 for Minaret WE-AG. The molecular weight range of the water-extractable arabinogalactan-peptide (WE-AGP) isolated from the different flour fractions of Camp Remy and Minaret was 5 x 10(4)-10 x 10(4). The 1H NMR spectra of the WE-AGP isolated from the different flour fractions were comparable and display the following diagnostic peaks (300 MHZ, D2O, 85 degrees C): delta 5.26, anomeric protons of alpha-lined arabinofuranosyl residues; and delta 4.47-4.54, anomeric protons of beta-linked galactose residues.status: publishe

Quantitative and qualitative study of arabinogalactan-peptide during bread making

The quantitative and qualitative changes of water-extractable arabinogalactan-peptide (WE-AGP) during a straight dough wheat bread-making process in the flour from two wheat varieties Skirlou and Soissons were investigated. The extractability of WE-AGP remains constant or increases slightly as a result of the bread-making process (increases of 12% for Skirlou and 10% for Soissons). This contrasts with the great increase in extractability of the water-extractable arabinoxylan (WE-AX) (29% for Skirlou and 77% for Soissons of the initially present WE-AX). No changes in arabinose substitution of WE-AX (0.47-0.50 for Skirlou, 0.52-0.54 for Soissons) and WE-AGP (0.66-0.70 for Skirlou, 0.69-0.72 for Soissons) occurred during the bread-making process. In contrast to differences found in molecular weight distribution of WE-AX, no differences in molecular weight distribution of WE-AGP as a result of processing were observed. Apparent molecular weights of 2.4 x 10(4) and 2.2 x 10(4) were found for WE-AGP samples of flour and doughs at different stages of the breadmaking process for Skirlou and Soissons, respectively. The H-1 NMR spectra (300 MHz, D2O, 85 degrees C) of the WE-AGP isolated from flour, dough, and bread fraction were comparable. Taken together, the above data suggest that, unlike what can be observed in gluten agglomeration in dilute systems (Roels, S. P., et al. J. Agric. Food Chem. 1998, 46, 1334-1343), there is no specific interaction between WE-AGP and gluten proteins in a straight dough bread-making process.status: publishe

Detection of Southern Asian Ovalocytosis with Sysmex XN‐10: A complement to the decision tree previously described

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Pancytopenia and megaloblastic erythropoiesis reveal a novel GIF mutation

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Early morphological diagnosis of Farber disease

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Detection of Minimal Residual Disease in B Cell Acute Lymphoblastic Leukemia Using an Eight-Color Tube with Dried Antibody Reagents

International audienceBackground Flow cytometry is a powerful tool for the detection of minimal residual disease (MRD) of B cell precursor acute lymphoblastic leukemia (BCP-ALL) patients. However, the staining process and the choice of antibodies rely on laboratory expertise and may be source of variability or technical errors. Recently, Beckman Coulter commercialized a ready to use tube with dried format reagents for BCP-ALL MRD detection. The aim of this study is to evaluate the applicability of this tube and to compare it to a conventional (liquid format reagents) method. Methods Thirty-one samples from B ALL patients were analyzed: 19 bone marrow (BM) aspirations, 10 peripheral blood (PB) samples and 2 cerebrospinal fluids at different stages of the follow-up. In addition, we tested 5 bone marrow samples mixed into non-pathological (control) bone marrow. The dried format tube included seven antibodies: CD45Kro, CD58FITC, CD34ECD, CD10PC5.5, CD19PC7, CD38AA700, CD20AA750, with possibility of additional antibodies for blast markers identified at diagnosis. For comparison, a liquid format tube was prepared, and considered as the reference. Results This tube was validated for daily routine laboratory, with satisfying qualitative (MRD + or MRD-) and quantitative (MRD percentages) correlation with the reference tube. Conclusion With this single dried format tube, we showed interesting results for BCP-ALL MRD detection in the aim of standardization and reliable interlaboratory results. It allows accurate MRD detection including low levels (10-4), and offers possibility to increase performance (supplementary antibody) within a preestablished effective antibody panel for BCP-ALL MRD. (c) 2018 International Clinical Cytometry Societ

Variation in the Degree of D-Xylose Substitution in Water-Extractable European Durum Wheat (Triticum Durum Desf.) Semolina Arabinoxylans

Durum wheat (Triticum durum Desf.) semolina water-extractable arabinoxylan (TWEAX) (yield 0.28%, arabinose-to-xylose ratio (A/X) 0. 62) was fractionated by a stepwise increase in ethanol concentration (up to 65%). The A/X ratios of the resulting fractions varied between 0.42 and 0.80. With increasing ethanol concentrations, increasing A/X ratios went hand in hand with a relative increase of low molecular weight compounds, indicating that high molecular weight compounds with a low A/X ratio are preferentially precipitated from alcohol/water mixtures. (1)H NMR showed that, whereas in TWEAX the levels of unsubstituted xyloses (X(0)), monosubstituted (X(1)), and disubstituted (X(2)) xyloses were 63.1%, 11.8%, and 25.1%, respectively, fractions that precipitated with increasing ethanol concentrations had decreasing levels of X(0). Simultaneously, the level of X(1) decreased equally until it leveled of at ca. 10%. Concomitantly, the level of X(2) increased. The levels of X(0), X(1), and X(2) varied between 69.7% and 53.4%, 18.2% and 10.7%, and 12.2% and 35.9%, respectively.status: publishe