Resistance to chemotherapeutic drugs is a major cause of treatment failure in Acute Myeloid Leukemias (AML). To better characterize the mechanisms of chemoresistance, we first identified genes whose expression is dysregulated in AML cells resistant to daunorubicin (DNR) or cytarabine (Ara-C), the main drugs used for the induction therapy. The genes found activated are mostly linked to immune signaling and inflammation. Among them, we identified a strong up-regulation of the NOX2 NAPDH oxidase subunit genes (CYBB, CYBA, NCF1, NCF2, NCF4 and RAC2). The ensuing increase in NADPH oxidase expression and ROS production, which is particularly strong in DNR-resistant cells, participates in the acquisition and/or maintenance of resistance to DNR. Gp91phox (CYBB-encoded Nox2 catalytic sub-unit), was found more expressed and active in leukemic cells from the FAB M4/M5 subtypes patients compared to FAB M0-M2 ones. Moreover, its expression was increased at the surface of patient’s chemotherapy resistant AML cells. Using a gene expression-based score we finally demonstrate that high NOX2 subunit genes expression is a marker of adverse prognosis in AML patients. The prognosis NOX score we defined is independent of the cytogenetic-based risk classification, FAB subtype, FLT3/NPM1 mutational status and age.
Background In fish, minimally invasive blood sampling is widely used to monitor physiological stress with blood plasma biomarkers. As fish blood cells are nucleated, they might be a source a potential new markers derived from ‘omics technologies. We modified the epiGBS (epiGenotyping By Sequencing) technique to explore changes in genome-wide cytosine methylation in the red blood cells (RBCs) of challenged European sea bass (Dicentrarchus labrax), a species widely studied in both natural and farmed environments. Results We retrieved 501,108,033 sequencing reads after trimming, with a mean mapping efficiency of 73.0% (unique best hits). Minor changes in RBC methylome appeared to manifest after the challenge test and a family-effect was detected. Only fifty-seven differentially methylated cytosines (DMCs) close to 51 distinct genes distributed on 17 of 24 linkage groups (LGs) were detected between RBCs of pre- and post-challenge individuals. Thirty-seven of these genes were previously reported as differentially expressed in the brain of zebrafish, most of them involved in stress coping differences. While further investigation remains necessary, few DMC-related genes associated to the Brain Derived Neurotrophic Factor, a protein that favors stress adaptation and fear memory, appear relevant to integrate a centrally produced stress response in RBCs. Conclusion Our modified epiGBS protocol was powerful to analyze patterns of cytosine methylation in RBCs of D. labrax and to evaluate the impact of a challenge using minimally invasive blood samples. This study is the first approximation to identify epigenetic biomarkers of exposure to stress in fish.
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