A transcriptomic continuum of differentiation arrest identifies myeloid interface acute leukemias with poor prognosis

Abstract: Classification of acute lymphoblastic and myeloid leukemias (ALL and AML) remains heavily based on phenotypic resemblance to normal hematopoietic precursors. This framework can provide diagnostic challenges for immunophenotypically heterogeneous immature leukemias, and ignores recent advances in understanding of developmental multipotency of diverse normal hematopoietic progenitor populations that are identified by transcriptional signatures. We performed transcriptional analyses of a large series of acute myeloid and lymphoid leukemias and detected significant overlap in gene expression between cases in different diagnostic categories. Bioinformatic classification of leukemias along a continuum of hematopoietic differentiation identified leukemias at the myeloid/T-lymphoid interface, which shared gene expression programs with a series of multi or oligopotent hematopoietic progenitor populations, including the most immature CD34+CD1a−CD7− subset of early thymic precursors. Within these interface acute leukemias (IALs), transcriptional resemblance to early lymphoid progenitor populations and biphenotypic leukemias was more evident in cases originally diagnosed as AML, rather than T-ALL. Further prognostic analyses revealed that expression of IAL transcriptional programs significantly correlated with poor outcome in independent AML patient cohorts. Our results suggest that traditional binary approaches to acute leukemia categorization are reductive, and that identification of IALs could allow better treatment allocation and evaluation of therapeutic options

A transcriptomic continuum of differentiation arrest identifies myeloid interface acute leukemias with poor prognosis

Abstract: Classification of acute lymphoblastic and myeloid leukemias (ALL and AML) remains heavily based on phenotypic resemblance to normal hematopoietic precursors. This framework can provide diagnostic challenges for immunophenotypically heterogeneous immature leukemias, and ignores recent advances in understanding of developmental multipotency of diverse normal hematopoietic progenitor populations that are identified by transcriptional signatures. We performed transcriptional analyses of a large series of acute myeloid and lymphoid leukemias and detected significant overlap in gene expression between cases in different diagnostic categories. Bioinformatic classification of leukemias along a continuum of hematopoietic differentiation identified leukemias at the myeloid/T-lymphoid interface, which shared gene expression programs with a series of multi or oligopotent hematopoietic progenitor populations, including the most immature CD34+CD1a−CD7− subset of early thymic precursors. Within these interface acute leukemias (IALs), transcriptional resemblance to early lymphoid progenitor populations and biphenotypic leukemias was more evident in cases originally diagnosed as AML, rather than T-ALL. Further prognostic analyses revealed that expression of IAL transcriptional programs significantly correlated with poor outcome in independent AML patient cohorts. Our results suggest that traditional binary approaches to acute leukemia categorization are reductive, and that identification of IALs could allow better treatment allocation and evaluation of therapeutic options

Les leucémies aiguës immatures à l interface myéloïde et lymphoïde T

Les leucémies aiguës résultent de la dérégulation de l homéostasie du tissu hématopoïétique, entrainant l expansion d un clone leucémique. Dans certains cas, l assignation de ces cellules à une voie de différenciation ne peut être faite de manière robuste par manque de marqueurs spécifiques d une lignée ou par expression simultanée de marqueurs lymphoïde T et myéloïde. Nous disposons d une cohorte de leucémies aiguës immatures lymphoïdes T (LAL-T) et myéloïdes (LAM0) et de leucémies dérivée des cellules dendritiques plasmocytoïdes (LpDC), nous permettant de mieux comprendre ces entités rares afin de contrer ces problèmes diagnostiques. Dans un premier temps nous avons adopté une approche transcriptomique, mettant en évidence un profil distinct pour les LpDC alors qu il n existe pas de frontière bien définie entre les LAL-T immatures et les LAM0. L analyse non supervisée des LAL-T ne respecte pas les sous-groupes de la classification immunogénétique10 ni même ceux de la classification EGIL5. De plus, certains cas de LAL-T immatures se classent au sein des LAM0, créant un groupe intermédiaire appelé mixte . L analyse bioinformatique de ces résultats a mis en évidence une liste de 124 gènes discriminants entre les entités immatures, dont LMO2 servira d exemple. Cependant il semble qu un seul transcrit ne permette pas aisément de caractériser ces entités, et qu une association de marqueurs soit nécessaire pour mieux les comprendre. Ainsi, les paramètres identifiés en transcriptome devraient à terme permettre l identification d un panel de marqueurs de cytométrie en flux assurant une orientation précoce des leucémies aiguës indifférenciées vers les protocoles de LAL ou de LAM. Dans un second temps nous avons recherché des stigmates d un engagement lymphoïde T et montré que les LAM0 et les LpDC peuvent présenter des réarrangements des TCR et , mais que les mutations activatrices de NOTCH1/FBXW7 restent un événement rare dans les LAM0. Nous avons démontré que le transcrit MEF2C est exprimé principalement dans les sous-populations thymiques humaines les plus immatures mais aussi dans les LAL-T immatures et de façon étonnante dans les LAM0. Enfin nous avons recherché des critères de mauvais pronostic des LAL-T immatures pédiatriques15 18 dans notre cohorte. L étude du critère ABD 18 (absence de délétion biallélique du TCR ) dans la série a permis de valider la concordance entre trois méthodes de détection des réarrangements du TCR . Les LAL-T immatures de l adulte répondent à la définition phénotypique et transcriptomique d une LAL-T ETP 15 (early-T-progenitor) mais leur pronostic est moins sévère. L analyse des courbes de survie du protocole GRAAL05 a mis en évidence que les LAL-T de l adulte peu différenciées répondent bien à ce type de chimiothérapieMONTPELLIER-BU Pharmacie (341722105) / SudocSudocFranceF

Gestion durable de la fertilité des sols par l'utilisation de matières organiques : retours d'expérience en Guyane française

Les sols sont au cœur des grands enjeux planétaires tels que la sécurité alimentaire et forment une ressource naturelle qu’il faut protéger et utiliser durablement. Afin de maintenir, voire d’améliorer, la fertilité des sols de Guyane déjà naturellement pauvres, des pratiques agro-écologiques, par valorisation d’apport en matières organiques (MO) permettant de stimuler la vie des sols, sont développées dans les systèmes de cultures actuels. Par cette approche de gestion durable, le sol n’est plus considéré comme un simple support mais comme un milieu vivant qui produit et fournit les éléments nutritifs aux cultures. Dans le cadre du projet Guyafer du RITA, différents types de matières organiques ont été testés (bois raméal fragmenté - BRF, charbon de bois, compost, plantes de couverture) pour en déterminer leur capacité à améliorer la qualité du sol. Cette qualité est appréhendée par l’utilisation de bio-indicateurs d’activités microbiennes du sol liées aux deux grands cycles biochimiques que sont ceux du carbone et de l’azote. Si les différents types de matières organiques amènent à des améliorations de la qualité des sols - la biomasse microbienne active du sol est souvent largement stimulée par l’apport de MO. Cette amélioration peut être très différente en intensité et en durée suivant le type de MO utilisée. Certains de ces apports n’entrainent pas de changement profond de la qualité, changement évalué par les indicateurs de variations de diversité.Soils are at the heart of major global challenges: food security, quality of groundwater and surface water, air quality, climate change and biodiversity. Soil is a natural resource that must be protected and sustainably used. To maintain or even improve the soil fertility of French Guiana, already naturally poor, agro-ecological processes focusing organic matter in order to stimulate the soil life are developed in the current cropping systems. Through this sustainable management approach, soil is no longer considered as an inert support but also as a living component that produces and provides nutrients to crops. Various types of organic matter (Rameal Chipped Wood - RCW, charcoal, compost, mulch of cover plants) were tested to determine their impact on the soil, particularly through the use of bio-indicators of soil microbial activities related to the carbon and nitrogen cycles. Every tested organic matters increase soil quality (high stimulation of active microbial biomass). However, different types of organic matters affect differently the soil microbial diversity

Gestion durable de la fertilité des sols par l'utilisation de matières organiques : retours d'expérience en Guyane française

Soils are at the heart of major global challenges: food security, quality of groundwater and surfacewater, air quality, climate change and biodiversity. Soil is a natural resource that must be protected andsustainably used. To maintain or even improve the soil fertility of French Guiana, already naturally poor,agro-ecological processes focusing organic matter in order to stimulate the soil life are developed in thecurrent cropping systems. Through this sustainable management approach, soil is no longer consideredas an inert support but also as a living component that produces and provides nutrients to crops.Various types of organic matter (Rameal Chipped Wood - RCW, charcoal, compost, mulch of coverplants) were tested to determine their impact on the soil, particularly through the use of bio-indicators ofsoil microbial activities related to the carbon and nitrogen cycles. Every tested organic matters increasesoil quality (high stimulation of active microbial biomass). However, different types of organic mattersaffect differently the soil microbial diversity.Les sols sont au cœur des grands enjeux planétaires tels que la sécurité alimentaire et forment uneressource naturelle qu’il faut protéger et utiliser durablement. Afin de maintenir, voire d’améliorer, lafertilité des sols de Guyane déjà naturellement pauvres, des pratiques agro-écologiques, parvalorisation d’apport en matières organiques (MO) permettant de stimuler la vie des sols, sontdéveloppées dans les systèmes de cultures actuels. Par cette approche de gestion durable, le sol n’estplus considéré comme un simple support mais comme un milieu vivant qui produit et fournit leséléments nutritifs aux cultures.Dans le cadre du projet Guyafer du RITA, différents types de matières organiques ont été testés (boisraméal fragmenté - BRF, charbon de bois, compost, plantes de couverture) pour en déterminer leurcapacité à améliorer la qualité du sol. Cette qualité est appréhendée par l’utilisation de bio-indicateursd’activités microbiennes du sol liées aux deux grands cycles biochimiques que sont ceux du carbone etde l’azote. Si les différents types de matières organiques amènent à des améliorations de la qualité dessols - la biomasse microbienne active du sol est souvent largement stimulée par l’apport de MO. Cetteamélioration peut être très différente en intensité et en durée suivant le type de MO utilisée. Certains deces apports n’entrainent pas de changement profond de la qualité, changement évalué par lesindicateurs de variations de diversité

Nitrogen cycling in the tropical rain forest of French Guiana: comparison of two sites with contrasting soil types using delta 15N

The natural 15N abundance method for estimating symbiotic biological N2-fixation was tested on legume trees from two rain forests on contrasting soils (oxisols and spodosols) in French Guiana. When possible, the significance of N2-fixing species in the plant community was evaluated in terms of density, biomass and contribution of N2-fixation to the building up of the total nitrogen mass in the leaves. Of the two sites, the rain forest on spodosols was the less favourable for application of the [delta]15N method: the available soil nitrogen was isotopically similar to fixed-N2. Hence, the results showed that a reliable estimate of N2-fixation could not be obtained. A substantial contribution of fixed-N2 to the nitrogen nutrition of legumes was found on oxisols, with an average value of 54 % Ndfa (Nitrogen derived from the atmosphere). The contribution of the N2-fixing legumes to the biomass of the stand was estimated to be 2 t ha[minus sign]1 for the leaf biomass and 136 t ha[minus sign]1 for the total above-ground plant biomass. With 7.5 % of trees in the stand able to fix N2 (462 out of 6156), N2-fixation was estimated to be 7 kg ha[minus sign]1 y[minus sign]1. These results are the first use of the [delta]15N method to estimate nitrogen input by N2-fixing legumes to a natural rain forest. The inter-site variability observed in the [delta]15N of the non-fixing plants suggested different nitrogen-cycling processes in the two soils. The [delta]15N of the non-N2-fixing plants could be related to the soil nitrogen availability and be used as an indicator of efficient or non-efficient nitrogen-cycling rain forests. The spatial variability of the [delta]15N in the plant-available soil nitrogen pool and the nitrogen balance in tropical rain forests are discussed

Evaluation of the recovery of microbial functions during soil restoration using near-infrared spectroscopy

Microbial-based indicators, such as C and N contents or microbial functions involved in C and N cycles, are currently used to describe the status of soils in disturbed areas. Microbial functions are more accurate indicators but their measurement for studies at the ecosystem level remains problematical because of the huge spatial variability of these processes and, consequently, of the large number of soil samples which must be analyzed. Our goal was to test the capacity of near-infrared reflectance spectroscopy (NIRS) to predict respiration and denitrification but also carbon and nitrogen contents of soils submitted to various procedures of restoration. To achieve this objective, we took advantage of an experiment conducted on a reforestation system established after open-cast gold mining in French Guiana. In this experimental station, plantations of various ages and various soil textures were at our disposal. Our results showed that both plantations and soil texture had a strong impact on the recovery of soil functioning: carbon and nitrogen contents, respiration and denitrification increased with age of plantation and clay content. Calibrations were performed between spectral data and microbial-based indicators using partial least squares regression (PLS). The results showed that C and N contents were accurately predicted. Microbial functions were less precisely predicted with results more accurate on clayey soils than on sandy soils. In clayey soils, perturbed or restored soils and the year of plantation were discriminated very efficiently through principal component analyses of spectral signatures (over 80% of variance explained on the first two axes). Near-infrared spectroscopy may thus be extended to the prediction of functional soil parameters, but the capacity of this method must be strengthened by expending the databases with other soils in other contexts. The possibility of using NIRS provides many opportunities for understanding both the temporal dynamics and the spatial variability of the recovery of key microbial functions during soil restoration

Microbial bioindicators of soil functioning after disturbance: The case of gold mining in tropical rainforests of French Guiana

In the context of an ongoing monitoring study on the impacts of gold-mining activities on critical ecosystem processes, we explored the use of soil Denitrifying Enzyme Activity (DEA) and Substrate Induced Respiration (SIR) as ecosystem indicators in tropical rainforests of French Guiana. We also propose DEA/SIR ratio as ecosystem attribute able to describe the state of an ecosystem and to reflect changes in ecological processes. With this purpose, we measured SIR, DEA and DEA/SIR ratio in five gold-mining areas and five surrounding natural reference rainforests. We also measured indicators in two conditions of spontaneous regeneration of vegetation (stratified or not) and two conditions of soil rehabilitation (prior preparation of soils or not). We showed a high variability of DEA, SIR and DEA/SIR ratio in the natural reference forests. This pointed out the necessity to identify relevant reference systems - i.e. proving a close match in all relevant ecological dimensions - to compare with closed perturbed systems in order to assess the levels of alterations after disturbances. Results showed a high impact of gold mine on microbial processes with a strong decrease of DEA (10-fold lower), SIR (2-fold lower) and DEA/SIR ratio (8-fold lower) in perturbed areas in comparison with natural reference forests. The type of spontaneous vegetation (stratified or not) influenced the values of indicators as well as prior rehabilitation of soils, demonstrating the capacity of DEA. SIR and DEA/SIR ratio to respond in proportion to the perturbation (robustness) and to the different levels of restoration (sensitivity). The systematic decrease of the ratio DEA/SIR observed in the studied perturbed situations demonstrates clearly that the structure of microbial communities has been also modified. The ratio DEA/SIR proved to be robust and sensitive, and able to describe in fairly fine way changes of soil microbial communities in terms of structure and function in gold mine areas and during processes of restoration. We propose to use DEA, SIR and DEA/SIR ratio as bioindicators of both structural and functional aspects of C and N cycling in soils. Together with others bioindicators based on key supporting functions in soils, these indicators should accurately evaluate the ecological potential of natural ecosystems and the levels of degradation in case of land-use changes. (C) 2012 Elsevier Ltd. All rights reserved

Leaf natural 15N abundance and total N concentration as potential indicators of plant N nutrition in legumes and pioneer species in a rain forest of French Guiana

The suitability of the natural 15N abundance and of total N concentration of leaves as indicators of the type of plant N nutrition in a rain forest of French Guiana were tested. Leaf samples from primary legume species, non-legumes (pioneer species) and from the non-N2-fixing species Dicorynia guianensis were analyzed. Both '15N and total leaf N varied widely (m1 r '15N (‰) r 7 and 1 r leaf N(%) r 3.2) suggesting possible distinctions between diazotrophic and non-fixing plants. The '15N also revealed two statistically distinct groups of non-N2-fixing species ('15N = 5.14 - 0.3 vs '15Nv=v1.65 - 0.17) related to the different ecological behaviors of these species in the successional processes. We conclude that the '15N signature of plant leaves combined with their total N concentration may be relevant indicators for identifying functional groups within the community of non-N2-fixing species, as well as for detecting diazotrophy. Despite the variability in the '15N of the non-N2-fixing species, N2-fixing groups can still be identified, provided that plants are simultaneously classified taxonomically, by their leaf '15N and total N concentration and by the presence or absence of nodules. The variability in the '15N of the non-fixing species is discussed

Nodulation and dinitrogen fixation of legume trees in a tropical freshwater swamp forest in French Guiana

Nodulated legume trees comprised 43% of the stand basal area in the low, most frequently flooded microsites, and 23% in higher, drier microsites in a tropical freshwater swamp forest in French Guiana. Dinitrogen fixation in Pterocarpus officinalis, Hydrochorea corymbosa and Inga pilosula was confirmed by acetylene reduction assay (ARA), presence of leghaemoglobin in nodules and the N-15 natural abundance method. The results for Zygia cataractae were inconclusive but suggested N-2 fixation in drier microsites. Nodulated Inga disticha had a N-15-to-N-14 ratio similar to non-N-2-fixing trees, but ARA indicated nitrogenase activity and leghaemoglobin was present in nodules. All bacterial strains were identified as Bradyrhizobium spp. according to the partial 16S rDNA sequences, and they were infective in vitro in the model species Macroptilium atropurpuretan. About 35-50% of N in the leaves of P. officinalis, H. corymbosa and I. pilosula was fixed from the atmosphere. Dinitrogen fixation was estimated to contribute at least 8-13% and 1728% to whole-canopy N in high and low microsites, respectively. Symbiotic N, fixation appears to provide both a competitive advantage to legume trees under N-limited, flooded conditions and an important N input to neotropical freshwater swamp forests