Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene-Driven Myeloid Leukemia.

Fusion oncogenes are prevalent in several pediatric cancers, yet little is known about the specific associations between age and phenotype. We observed that fusion oncogenes, such as ETO2-GLIS2, are associated with acute megakaryoblastic or other myeloid leukemia subtypes in an age-dependent manner. Analysis of a novel inducible transgenic mouse model showed that ETO2-GLIS2 expression in fetal hematopoietic stem cells induced rapid megakaryoblastic leukemia whereas expression in adult bone marrow hematopoietic stem cells resulted in a shift toward myeloid transformation with a strikingly delayed in vivo leukemogenic potential. Chromatin accessibility and single-cell transcriptome analyses indicate ontogeny-dependent intrinsic and ETO2-GLIS2-induced differences in the activities of key transcription factors, including ERG, SPI1, GATA1, and CEBPA. Importantly, switching off the fusion oncogene restored terminal differentiation of the leukemic blasts. Together, these data show that aggressiveness and phenotypes in pediatric acute myeloid leukemia result from an ontogeny-related differential susceptibility to transformation by fusion oncogenes. SIGNIFICANCE: This work demonstrates that the clinical phenotype of pediatric acute myeloid leukemia is determined by ontogeny-dependent susceptibility for transformation by oncogenic fusion genes. The phenotype is maintained by potentially reversible alteration of key transcription factors, indicating that targeting of the fusions may overcome the differentiation blockage and revert the leukemic state.See related commentary by Cruz Hernandez and Vyas, p. 1653.This article is highlighted in the In This Issue feature, p. 1631

Mesenchymal Transition and PDGFRA Amplification/Mutation Are Key Distinct Oncogenic Events in Pediatric Diffuse Intrinsic Pontine Gliomas

Diffuse intrinsic pontine glioma (DIPG) is one of the most frequent malignant pediatric brain tumor and its prognosis is universaly fatal. No significant improvement has been made in last thirty years over the standard treatment with radiotherapy. To address the paucity of understanding of DIPGs, we have carried out integrated molecular profiling of a large series of samples obtained with stereotactic biopsy at diagnosis. While chromosomal imbalances did not distinguish DIPG and supratentorial tumors on CGHarrays, gene expression profiling revealed clear differences between them, with brainstem gliomas resembling midline/thalamic tumours, indicating a closely-related origin. Two distinct subgroups of DIPG were identified. The first subgroup displayed mesenchymal and pro-angiogenic characteristics, with stem cell markers enrichment consistent with the possibility to grow tumor stem cells from these biopsies. The other subgroup displayed oligodendroglial features, and appeared largely driven by PDGFRA, in particular through amplification and/or novel missense mutations in the extracellular domain. Patients in this later group had a significantly worse outcome with an hazard ratio for early deaths, ie before 10 months, 8 fold greater that the ones in the other subgroup (p = 0.041, Cox regression model). The worse outcome of patients with the oligodendroglial type of tumors was confirmed on a series of 55 paraffin-embedded biopsy samples at diagnosis (median OS of 7.73 versus 12.37 months, p = 0.045, log-rank test). Two distinct transcriptional subclasses of DIPG with specific genomic alterations can be defined at diagnosis by oligodendroglial differentiation or mesenchymal transition, respectively. Classifying these tumors by signal transduction pathway activation and by mutation in pathway member genes may be particularily valuable for the development of targeted therapies

Flood frequency analysis in West Africa

Devastating flood events attributed to climate change have recently hit many West African countries. To mitigate the impact of such floods and reduce the vulnerability of populations, comprehensive insights into the frequency of these extreme events are crucial. The lack of reliable large-scale hydrometric datasets has hitherto been a major limitation in flood frequency analysis at the scale of West Africa. Utilizing a recently developed African database, we perform a flood frequency analysis on the annual maximum flow (AMF) time series, covering 246 river basins in West Africa, between 1975 and 2018. The trend analysis, performed with the non-parametric Mann-Kendall test, revealed some significant trends, with no discernible spatial pattern. Generalized extreme value (GEV) and Gumbel probability distributions were fitted to AMF time series using three parameter estimation methods: L-moments, Maximum Likelihood (MLE), and Generalized MLE (GMLE). The Akaike and Bayesian information criteria were used to compare the goodness-of-fit of probability distributions. Based on these evaluation criteria, the GEV distribution fitted with the GMLE method was selected as the best distribution in most stations. Furthermore, there was no significant difference between stationary and non-stationary quantiles of AMF series that exhibited a significant trend. Regional envelope curves, covering the entire West African region with unprecedented data coverage, have been generated for the first time. The correlation analysis between flood quantiles and watershed properties suggested stronger influences of physiographic and geological watershed properties than climate on regional variations in flood quantities. The findings from this study hold potential utility for flood risk assessment, design of hydraulic infrastructures, and water resources management. In addition, the probability distribution identified as the most suitable in this research might be favoured for regional flood frequency analysis in West Africa

Therapeutic potential of the human endogenous retroviral envelope protein HEMO: a pan‐cancer analysis

International audienc

Recent trends in vegetation cover and phenology in the southern Mediterranean region: Potential impacts on crop production and its link to changing climate extremes.

The southern Mediterranean region stands as one of the most vulnerable areas to climate change and variability in the world. There is a need for further understanding of the complex interactions between climate, vegetation, and crops to fully understand the combined impacts of extreme climate events on the agriculture sector. Using daily Normalized Difference Vegetation Index (NDVI) data, we evaluate recent trends across 15 vegetation phenology indicators between 1982 and 2019. Subsequently, we analyse potential links between recent trends in vegetation phenology and land-use land-cover. We found significant increasing trends in Maximum Value of NDVI (MaxV), length of growing season (LengthGS), and the time between the occurrence of the onset and maximum value (AreaB), especially within croplands. We also noted these vegetation phenological indicators, and their associated changes in the last 38 years, are significantly correlated with an increase in regional crop production. Then, we conducted a comprehensive seasonal trend analysis of extreme (potentially compound) climatic stresses and discussed how it aligns with recent trends in MaxV and LengthGS. We found that extended LengthGS and increased MaxV are consistent with increased precipitation and cooler temperatures during spring and summer, coupled with warmer autumn and winter trends. These trends collectively mitigate extreme heat, water, and compound heat-water stresses, contributing to improved crop yields over the region. By improving our understanding of the potential impacts of recent climate change on vegetation phenology, crop production and land use, our findings can help providing guidance for more informed decision-making and adaptation strategies in the southern Mediterranean region

Microtubule stabilizer ameliorates synaptic function and behavior in a mouse model for schizophrenia.

International audienceBACKGROUND: Recent data suggest that cytoskeletal defects may play a role in schizophrenia. We previously imitated features of schizophrenia in an animal model by disrupting gene coding for a microtubule-associated protein called STOP. STOP-null mice display synaptic defects in glutamatergic neurons, hyper-dopaminergy, and severe behavioral disorders. Synaptic and behavioral deficits are amended by neuroleptic treatment in STOP-null mice, providing an attractive model to test new antipsychotic agents. We examined the effects of a taxol-related microtubule stabilizer, epothilone D. METHODS: Mice were treated either with vehicle alone or with epothilone D. Treatment effects on synaptic function were assessed using electron-microscopy quantification of synaptic vesicle pools and electrophysiology in the CA1 region of the hippocampus. Dopamine transmission was investigated using electrochemical assays. Behavior was principally assessed using tests of maternal skills. RESULTS: In STOP-null mice, treatment with epothilone D increased synaptic vesicle pools, ameliorated both short- and long-term forms of synaptic plasticity in glutamatergic neurons, and had a dramatic beneficial effect on mouse behavior. CONCLUSIONS: A microtubule stabilizer can have a beneficial effect on synaptic function and behavior, suggesting new possibilities for treatment of schizophrenia

In-Vitro and In-Vivo Establishment and Characterization of Bioluminescent Orthotopic Chemotherapy-Resistant Human Osteosarcoma Models in NSG Mice

International audienceOsteosarcoma, the most common bone malignancy with a peak incidence at adolescence, had no survival improvement since decades. Persistent problems are chemo-resistance and metastatic spread. We developed in-vitro osteosarcoma models resistant to chemotherapy and in-vivo bioluminescent orthotopic cell-derived-xenografts (CDX). Continuous increasing drug concentration cultures in-vitro resulted in five methotrexate (MTX)-resistant and one doxorubicin (DOXO)-resistant cell lines. Resistance persisted after drug removal except for MG-63. Different resistance mechanisms were identified, affecting drug transport and action mechanisms specific to methotrexate (RFC/SCL19A1 decrease, DHFR up-regulation) for MTX-resistant lines, or a multi-drug phenomenon (PgP up-regulation) for HOS-R/DOXO. Differential analysis of copy number abnormalities (aCGH) and gene expression (RNAseq) revealed changes of several chromosomic regions translated at transcriptomic level depending on drug and cell line, as well as different pathways implicated in invasive and metastatic potential (e.g., Fas, Metalloproteinases) and immunity (enrichment in HLA cluster genes in 6p21.3) in HOS-R/DOXO. Resistant-CDX models (HOS-R/MTX, HOS-R/DOXO and Saos-2-B-R/MTX) injected intratibially into NSG mice behaved as their parental counterpart at primary tumor site; however, they exhibited a slower growth rate and lower metastatic spread, although they retained resistance and CGH main characteristics without drug pressure. These models represent valuable tools to explore resistance mechanisms and new therapies in osteosarcoma

Genomic aberrations in lung adenocarcinoma in never smokers.

BACKGROUND: Lung cancer in never smokers would rank as the seventh most common cause of cancer death worldwide. METHODS AND FINDINGS: We performed high-resolution array comparative genomic hybridization analysis of lung adenocarcinoma in sixty never smokers and identified fourteen new minimal common regions (MCR) of gain or loss, of which five contained a single gene (MOCS2, NSUN3, KHDRBS2, SNTG1 and ST18). One larger MCR of gain contained NSD1. One focal amplification and nine gains contained FUS. NSD1 and FUS are oncogenes hitherto not known to be associated with lung cancer. FISH showed that the amplicon containing FUS was joined to the next telomeric amplicon at 16p11.2. FUS was over-expressed in 10 tumors with gain of 16p11.2 compared to 30 tumors without that gain. Other cancer genes present in aberrations included ARNT, BCL9, CDK4, CDKN2B, EGFR, ERBB2, MDM2, MDM4, MET, MYC and KRAS. Unsupervised hierarchical clustering with adjustment for false-discovery rate revealed clusters differing by the level and pattern of aberrations and displaying particular tumor characteristics. One cluster was strongly associated with gain of MYC. Another cluster was characterized by extensive losses containing tumor suppressor genes of which RB1 and WRN. Tumors in that cluster frequently harbored a central scar-like fibrosis. A third cluster was associated with gains on 7p and 7q, containing ETV1 and BRAF, and displayed the highest rate of EGFR mutations. SNP array analysis validated copy-number aberrations and revealed that RB1 and WRN were altered by recurrent copy-neutral loss of heterozygosity. CONCLUSIONS: The present study has uncovered new aberrations containing cancer genes. The oncogene FUS is a candidate gene in the 16p region that is frequently gained in never smokers. Multiple genetic pathways defined by gains of MYC, deletions of RB1 and WRN or gains on 7p and 7q are involved in lung adenocarcinoma in never smokers

Long-term variability in hydrological droughts and floods in Sub-Saharan Africa: New Perspectives from a 65-year daily streamflow dataset

International audienceUnderstanding hydrological variability is of crucial importance for water resource management in sub-Saharan Africa (SSA). While existing studies typically focus on individual river basins, and suffer from incomplete records, this study provides a new perspective of trends and variability in hydrological flood and drought characteristics (frequency, duration, and intensity) across the entire SSA. This is achieved by: i) creating a 65-year long, complete daily streamflow dataset consisting of over 600 gauging stations; ii) quantifying changes in flood and drought characteristics between 1950 and 2014; iii) evaluating how decadal variability influences historical trends. Results of daily streamflow reconstructions using random forests provide satisfactory performance over most of SSA, except for parts of southern Africa. Using change-point and trend analyses, we identify-three periods that characterise historical variations affecting hydrological extremes in western and central Africa, and some parts of southern Africa: i) the 1950s-60s and after the 1980s-90s, when floods (droughts) tend to be more (less) intense, more (less) frequent and more (less) persistent; and ii) the 1970s-80s, when floods (droughts) are less (more) intense, less (more) frequent and less (more) persistent. Finally, we reveal significant decadal variations in all flood and drought characteristics, which explain aperiodic increasing and decreasing trends. This stresses the importance of considering multiple time-periods when analysing recent trends, as previous assessments may have been unrepresentative of long-term changes

Long-term variability in hydrological droughts and floods in sub-Saharan Africa: New perspectives from a 65-year daily streamflow dataset

International audienceUnderstanding hydrological variability is of crucial importance for water resource management in sub-Saharan Africa (SSA). While existing studies typically focus on individual river basins, and suffer from incomplete records, this study provides a new perspective of trends and variability in hydrological flood and drought characteristics (frequency, duration, and intensity) across the entire SSA. This is achieved by: i) creating a 65-year long, complete daily streamflow dataset consisting of over 600 gauging stations; ii) quantifying changes in flood and drought characteristics between 1950 and 2014; iii) evaluating how decadal variability influences historical trends. Results of daily streamflow reconstructions using random forests provide satisfactory performance over most of SSA, except for parts of southern Africa. Using change-point and trend analyses, we identify-three periods that characterise historical variations affecting hydrological extremes in western and central Africa, and some parts of southern Africa: i) the 1950s-60s and after the 1980s-90s, when floods (droughts) tend to be more (less) intense, more (less) frequent and more (less) persistent; and ii) the 1970s-80s, when floods (droughts) are less (more) intense, less (more) frequent and less (more) persistent. Finally, we reveal significant decadal variations in all flood and drought characteristics, which explain aperiodic increasing and decreasing trends. This stresses the importance of considering multiple time-periods when analysing recent trends, as previous assessments may have been unrepresentative of long-term changes