Phosphatases as New Druggable Targets in Acute Lymphoblastic Leukemia

Current chemotherapies in acute lymphoblastic leukemia (ALL) often cause sequelae in children and are ineffective against relapsed ALL. Molecularly targeted therapies are needed, yet most known oncogenic drivers of ALL are mis-expressed transcription factors that are not easily therapeutically targeted. Through a large-scale zebrafish screen, we have identified the phosphatase PRL3 as a novel driver of ALL progression and survival. PRL3 is highly expressed in ALL patient samples, and PRL3 knock-down or inhibition rapidly kills ALL cells in part through activation of p53. These data indicate that PRL3 plays an oncogenic role in ALL and is a suitable molecular target, yet phosphatases inhibitors have not been developed for cancer treatment. We propose to 1) test FDA-approved phosphatase inhibitors, some of which we know to inhibit PRL3, for anti-cancer activity in human ALL cells and in our zebrafish ALL model, and 2) identify and validate other phosphatases with oncogenic roles in ALL using a CRISPR-based screen and zebrafish transgenic models. Completion of this project will provide a strong scientific rationale phosphatases as a new class of molecular targets in cancer, and is likely to identify an FDA-approved phosphatase inhibitor that can be quickly entered into pre-clinical and clinical trials for ALL.