Zebrafish models uncover targetable mechanisms of self-renewal in Acute Lymphoblastic Leukemia

We used a zebrafish model of pediatric T-cell acute lymphoblastic leukemia (T-ALL) in large scale screening approaches to identify targetable drivers of leukemia stem cell self-renewal. In a transplantation screen, the phosphatase PRL-3 was recurrently amplified as zebrafish T-ALL gained enhanced self-renewal capability. We confirmed a role for PRL-3 in self-renewal using human cells lines and mouse xenograft. PRL-3’s active site has a shallow binding pocket and can be difficult to target with small molecules. We have developed several in vitro screening assays and are currently working to identify allosteric inhibitors (open to collaboration!). In a second project, using a large-scale FDA-repurposing screen in zebrafish T-ALL, we found the diuretic Amiloride significantly reduced self-renewal. We confirmed this in vitro, in human T-ALL cells. Preliminary experiments suggest that Amiloride targets the sodium/hydrogen exchanger NHE1 to disrupt mitochondrial function, which we have found to be particularly important for leukemia stem cell function, although current mechanisms are unknown. Finally, we will highlight some uses of zebrafish in pharmacology screening for anti-cancer compounds.