Corrigendum to "Analysis of reduced and oxidized antioxidants in Hevea brasiliensis latex reveals new insights into the regulation of antioxidants in response to harvesting stress and tapping panel dryness" [Heliyon 8 (7) (June 2022) Article e09840].

[This corrects the article DOI: 10.1016/j.heliyon.2022.e09840.].

Analysis of reduced and oxidized antioxidants in Hevea brasiliensis latex reveals new insights into the regulation of antioxidants in response to harvesting stress and tapping panel dryness.

Latex diagnosis (LD) is applied to optimize the natural rubber production and prevent tapping panel dryness (TPD), a physiological syndrome affecting latex production in Hevea brasiliensis. The reduced thiol content (RSH) is one of the biochemical parameters associated with the risk of TPD. However, RSH is difficult to interpret because of the influence of the environment. In order to better understand the regulation of antioxidants and to better interpret RSH, a key parameter of LD, this study analysed in latex both oxidised and reduced forms of ascorbic acid (AsA) and glutathione, and their cofactors as well as other latex diagnosis parameters in response to harvesting stress (tapping and ethephon stimulation) and TPD occurrence. The content of antioxidants in latex had a high variability among five rubber clones. The concentration in AsA was about ten times higher than GSH in laticifer, GSH accounting for about 50% of RSH. For short-term harvesting stress, RSH increased with tapping frequency and ethephon stimulation. TPD is associated with high latex viscosity and bursting of lysosomal particles called lutoids, as well as for several rubber clones with lower RSH and GSH contents. These results suggest that a high level of RSH shows the capacity of laticifer metabolism to cope with harvesting stress, while a drop in RSH is the sign of long stress related to lower metabolic activity and TPD occurrence. RSH remains an essential physiological parameter to prevent TPD when associated with reference data under low and high harvesting stress. This study paves the way to understand the role of AsA and GSH, and carry out genetic studies of antioxidants.

Cytolethal Distending Toxin Promotes Replicative Stress Leading to Genetic Instability Transmitted to Daughter Cells.

The cytolethal distending toxin (CDT) is produced by several Gram-negative pathogenic bacteria. In addition to inflammation, experimental evidences are in favor of a protumoral role of CDT-harboring bacteria such as Escherichia coli, Campylobacter jejuni, or Helicobacter hepaticus. CDT may contribute to cell transformation in vitro and carcinogenesis in mice models, through the genotoxic action of CdtB catalytic subunit. Here, we investigate the mechanism of action by which CDT leads to genetic instability in human cell lines and colorectal organoids from healthy patients' biopsies. We demonstrate that CDT holotoxin induces a replicative stress dependent on CdtB. The slowing down of DNA replication occurs mainly in late S phase, resulting in the expression of fragile sites and important chromosomic aberrations. These DNA abnormalities induced after CDT treatment are responsible for anaphase bridge formation in mitosis and interphase DNA bridge between daughter cells in G1 phase. Moreover, CDT-genotoxic potential preferentially affects human cycling cells compared to quiescent cells. Finally, the toxin induces nuclear distension associated to DNA damage in proliferating cells of human colorectal organoids, resulting in decreased growth. Our findings thus identify CDT as a bacterial virulence factor targeting proliferating cells, such as human colorectal progenitors or stem cells, inducing replicative stress and genetic instability transmitted to daughter cells that may therefore contribute to carcinogenesis. As some CDT-carrying bacterial strains were detected in patients with colorectal cancer, targeting these bacteria could be a promising therapeutic strategy.

Concurrent starch accumulation in stump and high fruit production in coffee (Coffea arabica).

In coffee, fruit production on a given shoot drops after some years of high yield, triggering pruning to induce resprouting. The timing of pruning is a crucial farmer's decision affecting yield and labour. One reason for fruit production drop could be the exhaustion of resources, particularly the non-structural carbohydrates (NSC). To test this hypothesis in a Coffea L. arabica agroforestry system, we measured the concentrations of NSC, carbon (C) and nitrogen (N) in leaves, stems and stumps of the coffee plants, 2 and 5 years after pruning. We also compared shaded vs full sun plants. For that purpose, both analytical reference and visible and near infrared reflectance spectroscopy (VNIRS) methods were used. As expected, concentrations of biochemical variables linked to photosynthesis activity (N, glucose, fructose, sucrose) decreased from leaves to stems, and then to stumps. In contrast, variables linked more closely to plant structure and reserves (total C, C:N ratio, starch concentration) were higher in long lifespan organs like stumps. Shading had little effect on most measured parameters, contrary to expectations. Concentrations of N, glucose and fructose were higher in 2-year-old organs. Conversely, starch concentration in perennial stumps was three times higher 5 years after pruning than 2 years after pruning, despite high fruit production. Therefore, the drop in fruit production occurring after 5-6 years was not due to a lack of NSC on plant scale. Starch accumulation in perennial organs concurrently to other sinks, such as fruit growth, could be considered as a 'survival' strategy, which may be a relic of the behaviour of wild coffee (a tropical shade-tolerant plant). This study confirmed that VNIRS is a promisingly rapid and cost-effective option for starch monitoring (coefficient of determination for validation, R2val = 0.91), whereas predictions were less accurate for soluble sugars, probably due to their too similar spectral signature.

GARP transcription factors repress Arabidopsis nitrogen starvation response via ROS-dependent and -independent pathways.

Plants need to cope with strong variations of nitrogen availability in the soil. Although many molecular players are being discovered concerning how plants perceive NO3- provision, it is less clear how plants recognize a lack of nitrogen. Following nitrogen removal, plants activate their nitrogen starvation response (NSR), which is characterized by the activation of very high-affinity nitrate transport systems (NRT2.4 and NRT2.5) and other sentinel genes involved in N remobilization such as GDH3. Using a combination of functional genomics via transcription factor perturbation and molecular physiology studies, we show that the transcription factors belonging to the HHO subfamily are important regulators of NSR through two potential mechanisms. First, HHOs directly repress the high-affinity nitrate transporters, NRT2.4 and NRT2.5. hho mutants display increased high-affinity nitrate transport activity, opening up promising perspectives for biotechnological applications. Second, we show that reactive oxygen species (ROS) are important to control NSR in wild-type plants and that HRS1 and HHO1 overexpressors and mutants are affected in their ROS content, defining a potential feed-forward branch of the signaling pathway. Taken together, our results define the relationships of two types of molecular players controlling the NSR, namely ROS and the HHO transcription factors. This work (i) up opens perspectives on a poorly understood nutrient-related signaling pathway and (ii) defines targets for molecular breeding of plants with enhanced NO3- uptake.

Genotypic variation in source and sink traits affects the response of photosynthesis and growth to elevated atmospheric CO2.

This study aimed to understand the response of photosynthesis and growth to e-CO2 conditions (800 vs. 400 µmol mol-1 ) of rice genotypes differing in source-sink relationships. A proxy trait called local C source-sink ratio was defined as the ratio of flag leaf area to the number of spikelets on the corresponding panicle, and five genotypes differing in this ratio were grown in a controlled greenhouse. Differential CO2 resources were applied either during the 2 weeks following heading (EXP1) or during the whole growth cycle (EXP2). Under e-CO2 , low source-sink ratio cultivars (LSS) had greater gains in photosynthesis, and they accumulated less nonstructural carbohydrate in the flag leaf than high source-sink ratio cultivars (HSS). In EXP2, grain yield and biomass gain was also greater in LSS probably caused by their strong sink. Photosynthetic capacity response to e-CO2 was negatively correlated across genotypes with local C source-sink ratio, a trait highly conserved across environments. HSS were sink-limited under e-CO2 , probably associated with low triose phosphate utilization (TPU) capacity. We suggest that the local C source-sink ratio is a potential target for selecting more CO2 -responsive cultivars, pending validation for a broader genotypic spectrum and for field conditions.

[Management of cancer patients with oral therapy at home in Brittany and Pays de la Loire areas: Survey (end of 2016) and cartography]. / Prise en charge des patients sous voies orales anticancéreuses au domicile en Bretagne et Pays de la Loire : enquête fin 2016 et cartographie.

INTRODUCTION: The Cancer Observatory, from the OMEDITs (Observatory for Medicines and Medical Devices and Treatment Innovations) of Bretagne and Pays de la Loire areas has conducted a survey aiming to know and map the current practices of management of patients by Oral Anti-cancer Drug (OAD) in inter-region. METHODS: Forty eight cancer centers received by e-mail in July and October 2016 a questionnaire concerning the management of OADs : from prescription by the specialist of oncology, to the intervention of the pharmacist (analysis and pharmaceutical consulting), to follow-up by nurse, as well as the financing of this activity and the feelings of the actors about this organizational set up. RESULTS: Fifty-seven professionals from 31 centers, including the most important ones, responded to the survey. As a result, half of the establishments carry out a pharmaceutical analysis for some or all of the OAD prescriptions and only 30% carry out a pharmaceutical consulting. The nurse consultation is, on the other hand, more largely implanted (74% of the centers) as well as the telephone follow-up (6%). More than 90% of professionals believe that the organizational set up could be improved and more secure by, at least, the stronger involvement of pharmacists, the development of tools for nurse (for monitoring, therapeutic education…) and by improving the city-hospital link. CONCLUSION: This survey shows the variability in the management of patients under OAD because of the lack of resources to ensure the fairness and sustainability of the organizational set up. The hospital/city link could still be optimized to secure patient care.

Is triose phosphate utilization involved in the feedback inhibition of photosynthesis in rice under conditions of sink limitation?

This study aimed to understand the physiological basis of rice photosynthetic response to C source-sink imbalances, focusing on the dynamics of the photosynthetic parameter triose phosphate utilization (TPU). Here, rice (Oriza sativa L.) indica cultivar IR64 were grown in controlled environment chambers under current ambient CO2 concentration until heading, and thereafter two CO2 treatments (400 and 800 µmol mol-1) were compared in the presence and absence of a panicle-pruning treatment modifying the C sink. At 2 weeks after heading, photosynthetic parameters derived from CO2 response curves, and non-structural carbohydrate content of flag leaf and internodes were measured three to four times of day. Spikelet number per panicle and flag leaf area on the main culm were recorded. Net C assimilation and TPU decreased progressively after midday in panicle-pruned plants, especially under 800 µmol mol-1 CO2. This TPU reduction was explained by sucrose accumulation in the flag leaf resulting from the sink limitation. Taking together, our findings suggest that TPU is involved in the regulation of photosynthesis in rice under elevated CO2 conditions, and that sink limitation effects should be considered in crop models.

A survey of the anesthetic management of pediatric kidney transplantation in France.

BACKGROUND: Renal transplantation is the best available therapeutic option for end-stage renal failure in both children and adults. However, little is known about anesthetic practice during pediatric renal transplantation. MATERIAL AND METHODS: The study consisted of a national survey about anesthetic practice during pediatric renal transplantation in France. French tertiary pediatric centers performing renal transplants were targeted, and one physician from each team was asked to complete the survey. The survey included patient data, preoperative assessment and optimization data, and intraoperative anesthesia data (drugs, ventilation, and hemodynamic interventions). RESULTS: Twenty centers performing kidney transplantation were identified and contacted to complete the survey, and eight responded. Surveyed centers performed 96 of the 122 pediatric kidney transplantations performed in France in 2017 (79%). Centers consistently performed echocardiography and ultrasound examinations of the great veins preoperatively and consistently employed esophageal Doppler cardiac output estimation and vasopressors intraoperatively. All other practices were found to be heterogeneous. Central venous pressure was monitored in six centers, and dopamine was administered perioperatively in two centers. CONCLUSIONS: The current study provides a snapshot of the perioperative management of pediatric kidney transplantation in France. Results emphasize the need for both standardization of practice and awareness of recent evidence against the use of CVP monitoring and dopamine infusions.

Exposure to the Fungicide Captan Induces DNA Base Alterations and Replicative Stress in Mammalian Cells.

The classification of the fungicide captan (CAS Number: 133-06-2) as a carcinogen agent is presently under discussion. Despite the mutagenic effect detected by the Ames test and carcinogenic properties observed in mice, the genotoxicity of this pesticide in humans is still unclear. New information is needed about its mechanism of action in mammalian cells. Here, we show that Chinese Hamster Ovary (CHO) cells exposed to captan accumulate Fpg-sensitive DNA base alterations. In CHO and HeLa cells, such DNA lesions require the XRCC1-dependent pathway to be repaired. Captan also induces a replicative stress that activated the ATR signaling response and resulted in double-strand breaks and micronuclei. The replicative stress is characterized by a dramatic decrease in DNA synthesis due to a reduced replication fork progression. However, impairment of the XRCC1-related repair process did not amplify the replicative stress, suggesting that the fork progression defect is independent from the presence of base modifications. These results support the involvement of at least two independent pathways in the genotoxic effect of captan that might play a key role in carcinogenesis. Environ. Mol. Mutagen. 60:286-297, 2019. © 2018 Wiley Periodicals, Inc.

Growth and carbon balance are differently regulated by tree and shoot fruiting contexts: an integrative study on apple genotypes with contrasted bearing patterns.

In plants, carbon source-sink relationships are assumed to affect their reproductive effort. In fruit trees, carbon source-sink relationships are likely to be involved in their fruiting behavior. In apple, a large variability in fruiting behaviors exists, from regular to biennial, which has been related to the within-tree synchronization vs desynchronization of floral induction in buds. In this study, we analyzed if carbon assimilation, availability and fluxes as well as shoot growth differ in apple genotypes with contrasted behaviors. Another aim was to determine the scale of plant organization at which growth and carbon balance are regulated. The study was carried out on 16 genotypes belonging to three classes: (i) biennial, (ii) regular with a high production of floral buds every year and (iii) regular, displaying desynchronized bud fates in each year. Three shoot categories, vegetative and reproductive shoots with or without fruits, were included. This study shows that shoot growth and carbon balance are differentially regulated by tree and shoot fruiting contexts. Shoot growth was determined by the shoot fruiting context, or by the type of shoot itself, since vegetative shoots were always longer than reproductive shoots whatever the tree crop load. Leaf photosynthesis depended on the tree crop load only, irrespective of the shoot category or the genotypic class. Starch content was also strongly affected by the tree crop load with some adjustments of the carbon balance among shoots since starch content was lower, at least at some dates, in shoots with fruits compared with the shoots without fruits within the same trees. Finally, the genotypic differences in terms of shoot carbon balance partly matched with genotypic bearing patterns. Nevertheless, carbon content in buds and the role of gibberellins produced by seeds as well as the distances at which they could affect floral induction should be further analyzed.

Overexpression of Hevea brasiliensis ethylene response factor HbERF-IXc5 enhances growth and tolerance to abiotic stress and affects laticifer differentiation.

Ethylene response factor 1 (ERF1) is an essential integrator of the jasmonate and ethylene signalling pathways coordinating a large number of genes involved in plant defences. Its orthologue in Hevea brasiliensis, HbERF-IXc5, has been assumed to play a major role in laticifer metabolism and tolerance to harvesting stress for better latex production. This study sets out to establish and characterize rubber transgenic lines overexpressing HbERF-IXc5. Overexpression of HbERF-IXc5 dramatically enhanced plant growth and enabled plants to maintain some ecophysiological parameters in response to abiotic stress such as water deficit, cold and salt treatments. This study revealed that HbERF-IXc5 has rubber-specific functions compared to Arabidopsis ERF1 as transgenic plants overexpressing HbERF-IXc5 accumulated more starch and differentiated more latex cells at the histological level. The role of HbERF-IXc5 in driving the expression of some target genes involved in laticifer differentiation is discussed.

Around and beyond 53BP1 Nuclear Bodies.

Within the nucleus, sub-nuclear domains define territories where specific functions occur. Nuclear bodies (NBs) are dynamic structures that concentrate nuclear factors and that can be observed microscopically. Recently, NBs containing the p53 binding protein 1 (53BP1), a key component of the DNA damage response, were defined. Interestingly, 53BP1 NBs are visualized during G1 phase, in daughter cells, while DNA damage was generated in mother cells and not properly processed. Unlike most NBs involved in transcriptional processes, replication has proven to be key for 53BP1 NBs, with replication stress leading to the formation of these large chromatin domains in daughter cells. In this review, we expose the composition and organization of 53BP1 NBs and focus on recent findings regarding their regulation and dynamics. We then concentrate on the importance of the replication stress, examine the relation of 53BP1 NBs with DNA damage and discuss their dysfunction.

Plasticity of Sorghum Stem Biomass Accumulation in Response to Water Deficit: A Multiscale Analysis from Internode Tissue to Plant Level.

Sorghum is increasingly used as a biomass crop worldwide. Its genetic diversity provides a large range of stem biochemical composition suitable for various end-uses as bioenergy or forage. Its drought tolerance enables it to reasonably sustain biomass production under water limited conditions. However, drought effect on the accumulation of sorghum stem biomass remains poorly understood which limits progress in crop improvement and management. This study aimed at identifying the morphological, biochemical and histological traits underlying biomass accumulation in the sorghum stem and its plasticity in response to water deficit. Two hybrids (G1, G4) different in stem biochemical composition (G4, more lignified, less sweet) were evaluated during 2 years in the field in Southern France, under two water treatments differentiated during stem elongation (irrigated; 1 month dry-down until an average soil water deficit of -8.85 bars). Plant phenology was observed weekly. At the end of the water treatment and at final harvest, plant height, stem and leaf dry-weight and the size, biochemical composition and tissue histology of internodes at 2-4 positions along the stem were measured. Stem biomass accumulation was significantly reduced by drought (in average 42% at the end of the dry-down). This was due to the reduction of the length, but not diameter, of the internodes expanded during water deficit. These internodes had more soluble sugar but lower lignin and cellulose contents. This was associated with a decrease of the areal proportion of lignified cell wall in internode outer zone whereas the areal proportion of this zone was not affected. All internodes for a given genotype and environment followed a common histochemical dynamics. Hemicellulose content and the areal proportion of inner vs. outer internode tissues were set up early during internode growth and were not drought responsive. G4 exhibited a higher drought sensitivity than G1 for plant height only. At final harvest, the stem dry weight was only 18% lower in water deficit (re-watered) compared to well-watered treatment and internodes growing during re-watering were similar to those on the well-watered plants. These results are being valorized to refine the phenotyping of sorghum diversity panels and breeding populations.

Influence of the radial stem composition on the thermal behaviour of miscanthus and sorghum genotypes.

The hypothesis made is that thermal resistance of sorghum and miscanthus stem pieces taken at well-defined positions of the stem is simply related to their biochemical composition. For miscanthus, two different genotypes and two internode levels were selected. For each region, the stem was divided into three radial layers. For sorghum, two different genotypes were selected and the stem was divided into the same three radial layers. The results show that the thermal analysis is only sensitive to very large variations of compositions. But aside of such large composition differences, it is impossible to correlate thermal effects to biochemical composition even on very small size, well-identified pieces of plant materials. The interplay between sugar-based components, lignin and minerals is totally blurring the thermal response. Extreme care must be exercised when willing to explain why a given plant material has a thermal behaviour different of another plant material.

Increased light-use efficiency sustains net primary productivity of shaded coffee plants in agroforestry system.

In agroforestry systems, shade trees strongly affect the physiology of the undergrown crop. However, a major paradigm is that the reduction in absorbed photosynthetically active radiation is, to a certain extent, compensated by an increase in light-use efficiency, thereby reducing the difference in net primary productivity between shaded and non-shaded plants. Due to the large spatial heterogeneity in agroforestry systems and the lack of appropriate tools, the combined effects of such variables have seldom been analysed, even though they may help understand physiological processes underlying yield dynamics. In this study, we monitored net primary productivity, during two years, on scales ranging from individual coffee plants to the entire plot. Absorbed radiation was mapped with a 3D model (MAESPA). Light-use efficiency and net assimilation rate were derived for each coffee plant individually. We found that although irradiance was reduced by 60% below crowns of shade trees, coffee light-use efficiency increased by 50%, leaving net primary productivity fairly stable across all shade levels. Variability of aboveground net primary productivity of coffee plants was caused primarily by the age of the plants and by intraspecific competition among them (drivers usually overlooked in the agroforestry literature) rather than by the presence of shade trees.

Genetic Determinism of Sensitivity to Corynespora cassiicola Exudates in Rubber Tree (Hevea brasiliensis).

An indirect phenotyping method was developed in order to estimate the susceptibility of rubber tree clonal varieties to Corynespora Leaf Fall (CLF) disease caused by the ascomycete Corynespora cassiicola. This method consists in quantifying the impact of fungal exudates on detached leaves by measuring the induced electrolyte leakage (EL%). The tested exudates were either crude culture filtrates from diverse C. cassiicola isolates or the purified cassiicolin (Cas1), a small secreted effector protein produced by the aggressive isolate CCP. The test was found to be quantitative, with the EL% response proportional to toxin concentration. For eight clones tested with two aggressive isolates, the EL% response to the filtrates positively correlated to the response induced by conidial inoculation. The toxicity test applied to 18 clones using 13 toxinic treatments evidenced an important variability among clones and treatments, with a significant additional clone x treatment interaction effect. A genetic linkage map was built using 306 microsatellite markers, from the F1 population of the PB260 x RRIM600 family. Phenotyping of the population for sensitivity to the purified Cas1 effector and to culture filtrates from seven C. cassiicola isolates revealed a polygenic determinism, with six QTL detected on five chromosomes and percentages of explained phenotypic variance varying from 11 to 17%. Two common QTL were identified for the CCP filtrate and the purified cassiicolin, suggesting that Cas1 may be the main effector of CCP filtrate toxicity. The CCP filtrate clearly contrasted with all other filtrates. The toxicity test based on Electrolyte Leakage Measurement offers the opportunity to assess the sensitivity of rubber genotypes to C. cassiicola exudates or purified effectors for genetic investigations and early selection, without risk of spreading the fungus in plantations. However, the power of this test for predicting field susceptibility of rubber clones to CLF will have to be further investigated.

CHK1 as a therapeutic target to bypass chemoresistance in AML.

The nucleoside analog cytarabine, an inhibitor of DNA replication fork progression that results in DNA damage, is currently used in the treatment of acute myeloid leukemia (AML). We explored the prognostic value of the expression of 72 genes involved in various aspects of DNA replication in a set of 198 AML patients treated by cytarabine-based chemotherapy. We unveiled that high expression of the DNA replication checkpoint gene CHEK1 is a prognostic marker associated with shorter overall, event-free, and relapse-free survivals and determined that the expression of CHEK1 can predict more frequent and earlier postremission relapse. CHEK1 encodes checkpoint kinase 1 (CHK1), which is activated by the kinase ATR when DNA replication is impaired by DNA damage. High abundance of CHK1 in AML patient cells correlated with higher clonogenic ability and more efficient DNA replication fork progression upon cytarabine treatment. Exposing the patient cells with the high abundance of CHK1 to SCH900776, an inhibitor of the kinase activity of CHK1, reduced clonogenic ability and progression of DNA replication in the presence of cytarabine. These results indicated that some AML cells rely on an efficient CHK1-mediated replication stress response for viability and that therapeutic strategies that inhibit CHK1 could extend current cytarabine-based treatments and overcome drug resistance. Furthermore, monitoring CHEK1 expression could be used both as a predictor of outcome and as a marker to select AML patients for CHK1 inhibitor treatments.

The qTSN4 Effect on Flag Leaf Size, Photosynthesis and Panicle Size, Benefits to Plant Grain Production in Rice, Depending on Light Availability.

Increasing rice yield potential is essential to secure world food supply. The quantitative trait locus qTSN4 was reported to achieve yield increases by enhancing both source and sink capacity. Three greenhouse experiments and one field experiment in the Philippines were conducted to study near-isogenic lines (NILs) in two genetic backgrounds, subjected to treatments with restricted light resources through shading (greenhouse) or population density (field and greenhouse). A consistent promotion of flag leaf width, leaf area and panicle size in terms of spikelet number was observed in the presence of qTSN4, regardless of environment. However, grain production per plant was enhanced only in one greenhouse experiment. An in-depth study demonstrated that increased flag leaf size in the presence of qTSN4 was associated with increased photosynthetic rates, along with lower SLA and greater N content per leaf weight and per area. This was emphasized under low light situation as the qTSN4-NILs did not express shade acclimation traits in contrast with the recipient varieties. The authors conclude that qTSN4 is a promising subject for further physiological studies, particularly under limited radiation. However, the QTL alone may not be a reliable source of increased yield potential because its effects at the plant and population scale are prone to genotype × environment interactions and the increased panicle size is compensated by the adaptive plasticity of other morphological traits.

CDC25A governs proliferation and differentiation of FLT3-ITD acute myeloid leukemia.

We investigated cell cycle regulation in acute myeloid leukemia cells expressing the FLT3-ITD mutated tyrosine kinase receptor, an underexplored field in this disease. Upon FLT3 inhibition, CDC25A mRNA and protein were rapidly down-regulated, while levels of other cell cycle proteins remained unchanged. This regulation was dependent on STAT5, arguing for FLT3-ITD-dependent transcriptional regulation of CDC25A. CDC25 inhibitors triggered proliferation arrest and cell death of FLT3-ITD as well as FLT3-ITD/TKD AC-220 resistant cells, but not of FLT3-wt cells. Consistently, RNA interference-mediated knock-down of CDC25A reduced the proliferation of FLT3-ITD cell lines. Finally, the clonogenic capacity of primary FLT3-ITD AML cells was reduced by the CDC25 inhibitor IRC-083864, while FLT3-wt AML and normal CD34+ myeloid cells were unaffected. In good agreement, in a cohort of 100 samples from AML patients with intermediate-risk cytogenetics, high levels of CDC25A mRNA were predictive of higher clonogenic potential in FLT3-ITD+ samples, not in FLT3-wt ones.Importantly, pharmacological inhibition as well as RNA interference-mediated knock-down of CDC25A also induced monocytic differentiation of FLT3-ITD positive cells, as judged by cell surface markers expression, morphological modifications, and C/EBPα phosphorylation. CDC25 inhibition also re-induced monocytic differentiation in primary AML blasts carrying the FLT3-ITD mutation, but not in blasts expressing wild type FLT3. Altogether, these data identify CDC25A as an early cell cycle transducer of FLT3-ITD oncogenic signaling, and as a promising target to inhibit proliferation and re-induce differentiation of FLT3-ITD AML cells.