Project description:T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy commonly driven by NOTCH1 activating mutations. A concomitant feature associated with NOTCH1 mutations is heightened oxidative metabolism enabling the exponential proliferation of T-ALL blasts. As such, targeting mitochondrial metabolism in T-ALL is an attractive therapeutic avenue. Canagliflozin (cana) is an FDA-approved sodium glucose co-transporter 2 inhibitor with known off-target effects on complex I and glutamate dehydrogenase. To date, the effects of cana on T-ALL are not known. Here, we show that cana possesses potent anti-leukaemic effects underpinned by proliferative defects, cell cycle disruption and apoptosis. These anti-leukaemic effects, driven by cana, are attributed to a perturbed tricarboxylic acid (TCA) cycle and mitochondrial metabolism and elevated mitochondrial ROS. Proteomic analysis revealed that cana treatment resulted in a compensatory increase in the expression of ATF4 targets, including upregulation of serine biosynthesis pathway and one-carbon metabolism enzymes. As such, restriction of serine and glycine synergized with cana treatment, further enhancing anti-leukaemic effects. Collectively, our study reveals cana creates a metabolic vulnerability that can be further exploited via dietary manipulation to treat T-ALL
Project description:The miRNAs expression profile of four typical stages of tooth development, embryonic day 35 (E35), E45, E50, and E60, which cover the major morphological and physiological changes in pig tooth germ growth and development throughout pregnancy, including the bud, cap, early bell, and late bell stages.
