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Leukemia stem cells (LSCs) are thought to drive the genesis of acute myeloid leukemia (AML) as well as relapse following chemotherapy. Because of their unique biology, developing effective methods to eradicate LSCs has been a significant challenge. In the present study, we demonstrate that intrinsic overexpression of the mitochondrial dynamics regulator FIS1 mediates mitophagy activity that is essential for primitive AML cells. Depletion of FIS1 attenuates mitophagy and leads to inactivation of GSK3, myeloid differentiation, cell cycle arrest, and a profound loss of LSC self-renewal potential. Further, we report that the central metabolic stress regulator AMPK is also intrinsically activated in LSC populations and is upstream of FIS1. Inhibition of AMPK signaling recapitulates the biological effect of FIS1 loss. These data suggest a model in which LSCs co-opt AMPK/FIS1-mediated mitophagy as a means to maintain stem cell properties that may be otherwise compromised by the stresses induced by oncogenic transformation.

[blank pages: 18, 38, 54 & 70], Rheological property such as shear viscosity and flow curve for metallic liquid systems has been evaluated. Pure Al, pure Zn, Sn based solder alloy and various compositions of Al-Si hypoeutectic binary alloys were the metallic systems included in the study. The effect of 0.023 wt % Sr edition to various compositions of Al-Si composition and shear rate experience by the liquid. A rotational rheometer was developed with a high temperature environmental furnace for this study. Three types of measurement geometry were evaluated: cone and plate, Din Coaxial and Double Concentric Cylinder (DCC). The DCC geometry has been proposed as the most practical geometry for liquid metal viscosity measurement in rotational rheometer. Analytical solution to evaluate viscosity with the rotational rheometer equipped with DCC measurement has been proposed. Further, the critical maximum allowable angular velocity for reliable viscosity evaluation has also been proposed for this system. It has been concluded that contrary to popular belief, liquid metal systems are non-Newtonian and shear thinning fluids. The effect of Si on the viscosity of Al-Si hypoeutectic alloys have been quantified as a function of shear rate and melt super heat temperatures. Further, it has been concluded that Sr additional to Al-Si alloys significantly alters the viscosity and the melt at low melt super heat temperatures., Master of Applied Science (MASc)