Identification of Hepatic Niche Harboring Human Acute Lymphoblastic Leukemic Cells via the SDF-1/CXCR4 Axis

In acute lymphoblastic leukemia (ALL) patients, the bone marrow niche is widely known to be an important element of treatment response and relapse. Furthermore, a characteristic liver pathology observed in ALL patients implies that the hepatic microenvironment provides an extramedullary niche for leukemic cells. However, it remains unclear whether the liver actually provides a specific niche. The mechanism underlying this pathology is also poorly understood. Here, to answer these questions, we reconstituted the histopathology of leukemic liver by using patients-derived primary ALL cells into NOD/SCID/Yc null mice. The liver pathology in this model was similar to that observed in the patients. By using this model, we clearly demonstrated that bile duct epithelial cells form a hepatic niche that supports infiltration and proliferation of ALL cells in the liver. Furthermore, we showed that functions of the niche are maintained by the SDF-1/CXCR4 axis, proposing a novel therapeutic approach targeting the extramedullary niche by inhibition of the SDF-1/CXCR4 axis. In conclusion, we demonstrated that the liver dissemination of leukemia is not due to nonselective infiltration, but rather systematic invasion and proliferation of leukemic cells in hepatic niche. Although the contribution of SDF-1/CXCR4 axis is reported in some cancer cells or leukemic niches such as bone marrow, we demonstrated that this axis works even in the extramedullary niche of leukemic cells. Our findings form the basis for therapeutic approaches that target the extramedullary niche by inhibiting the SDF-1/CXCR4 axis

Effect of Uniaxial Fatigue Aging and Fabric Orientation on Low Impact Velocity Response of Glass Fibers/Elium Acrylic Composite Laminates

Impact resistance is one of the most critical features of composite structures, and therefore, its examination for a new material has a fundamental importance. This paper is devoted to the characterization of the fully recyclable thermoplastic ELIUM acrylic resin reinforced by glass fabric woven, which belongs to a new category of materials requiring advanced testing before their application in responsible elements of engineering structures. Its high strength, low weight as well as low production cost give excellent opportunities for its wide application in the automotive industry as a replacement of the thermoset-based laminates. The study presents an experimental work concerning the effect of damage due to low and high cyclic fatigue aging of two groups of specimens, first with the woven fabric orientations of [0°/90°]4 and secondly with [45°/45°]4, on the low impact velocity properties. The impact resistance was measured in terms of load peak, absorbed energy, penetration threshold and damage analysis. The low velocity impact results indicate that the uniaxial cyclic loading (fatigue aging) of the material leads to the reduction of impact resistance, especially at the high impact energy levels. Scanning Electron Microscopy (SEM) and Computed Tomography (CT) scan observations reveal that the damage area grows with the increase of both strain amplitude and impact energy

Receptor kinase profiles identify a rationale for multitarget kinase inhibition in immature T-ALL.

International audienceConstitutively activated FLT3 signaling is common in acute myeloid leukemia, and is currently under evaluation for targeted therapy, whereas little data is available in T-cell acute lymphoblastic leukemia (T-ALL). We analyzed 357 T-ALL cases for FLT3 mutations and transcript expression. FLT3 mutations (3% overall) and overexpression (FLT3 high expresser (FLT3(High))) were restricted to imnnature/TCR gamma delta T-ALLs. In vitro FLT3 inhibition induced apoptosis in only 30% of FLT3(High) T-ALLs and did not correlate with mutational status. In order to investigate the mechanisms of primary resistance to FLT3 inhibition, a broad quantitative screen for receptor kinome transcript deregulation was performed by Taqman Low Density Array. FLT3 deregulation was associated with overexpression of a network of receptor kinases (RKs), potentially responsible for redundancies and sporadic response to specific FLT3 inhibition. In keeping with this resistance to FLT3 inhibition could be reversed by dual inhibition of FLT3 and KIT with a synergistic effect. We conclude that immature T-ALL may benefit from multitargeted RK inhibition and that exploration of the receptor kinome defines a rational strategy for testing multitarget kinase inhibition in malignant disease

Receptor kinase profiles identify a rationale for multi-target kinase inhibition in immature T-ALL.

International audienc

Receptor kinase profiles identify a rationale for multi-target kinase inhibition in immature T-ALL.

International audienc