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* < 0.05. MAPK pathways are known to be activated by ROS, and more particularly p38MAPK, the inactivation of which is associated with self-renewal of normal and leukemic HSCs [13,20,23]. could be involved in the regulation of leukemogenesis. Sauvageau et al. have reported a GPx-3/ROS/p38 MAPK axis which controls the aggressiveness of leukemia. In this model, GPX3 overexpressing LICs display low ROS levels associated with an inactivation of p38 MAPK [23]. Moreover, the importance of in AML biology is usually highlighted by the fact that this same authors exhibited that the highest levels of GPX3 in primary human AML cells are from patients with adverse prognosis, classically associated with a high frequency of LICs [26]. More broadly, when considering energy metabolism in hematopoietic cells, HSCs exhibit lower mitochondrial respiration and respiratory capacities than progenitors cells [27], which is essential for their maintenance and long-term function [28,29,30,31]. In MK-2206 2HCl addition, Ito et al. showed that mitophagy participates in their self-renewal by degrading defective mitochondria [32]. During cell differentiation, the energy demand increases, making it necessary to accelerate the mitochondrial metabolism which promotes entry into the cell cycle as well as differentiation [33], in particular via an increase DP3 in ROS levels [34]. Conversely to normal hematopoiesis, leukemic cells present a differential sensitivity to modulators of glycolysis, which is usually involved in the initiation and maintenance of leukemia [35], as well as in drug resistance [36,37]. Moreover, AML cells (bulk) MK-2206 2HCl have a higher mitochondrial mass and an increased oxygen consumption rate in comparison to normal hematopoietic progenitors. Interestingly, mitochondrial and oxidative phosphorylation system (OXPHOS) activities have been reported as major MK-2206 2HCl regulators of chemoresistance in leukemic cells [38]. Finally, a recent publication by the group of Tonks established for the first time the relationship between ROS production and glycolysis to promote the proliferation of leukemic cells via PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 enzyme) overexpression [39]. The aim of this study was to characterize the GPx3/ROS/p38MAPK axis and associated molecular pathways in cell partners of the leukemic niche before chemotherapy. The spread of leukemic cells in different sites of hematopoiesis leads them to interact with an initially nonleukemic hematopoietic microenvironment, which will promote leukemic development within specific niches. Using a model of leukemic niche established by coculturing primary BM mesenchymal stromal cells (MSCs) and AML cells, we established that this BM-MSCs contact promotes in leukemic cells an overexpression of GPX3, a decrease in ROS levels, the cytoplasmic relocalization of Nrf2, and an inactivation of p38MAPK. The concomitant inhibition of their proliferation was associated with a reduction of their energy/redox metabolism. Interestingly, reverse effects were observed in BM-MSCs for which the contact with leukemic cells promotes a decrease in GPX3 expression, higher ROS levels, and nuclear relocalization of Nrf2. 2. Results 2.1. Primary Bone Marrow MSCs Reduce the Proliferation of Leukemic Cells The effects of MSCs around the growth of leukemic cells of the AML KG1a MK-2206 2HCl cell-line were studied after 72h of culture in BM MSC-conditioned medium (MSC-CM) with or without contact with MSCs (Physique 1A). MSC-CM did not modify the growth of leukemic cells which was conversely was significantly MK-2206 2HCl decreased in the presence of MSCs in the culture system (Physique 1B; < 0.0001). This indicates that MSC contact is necessary to control leukemia proliferation [40]. An original flow cytometry method was developed to precisely discriminate all the cell cycle phases and apoptosis of leukemic cells [41]. MSC-CM did.