The Tyrosine Phosphatase PRL3 Drives T‐Cell Acute Lymphoblastic Leukemia Progression

Abstract

T‐cell acute lymphoblastic leukemia (T‐ALL) is a major clinical challenge, representing 15–25% of all acute lymphoblastic leukemias in children and adults. The survival rate for pediatric patients with relapsed T‐ALL is a disheartening <30% in pediatric patients and <10% in adults. Current drugs against T‐ALL include highly cytotoxic chemotherapies, which are generally ineffective against relapse and are particularly hard for young children to receive. These harsh therapies can result in a spectrum of developmental issues and potent side‐effects. Therefore, it is imperative to develop molecularly targeted therapies that can effectively inhibit T‐ALL progression without contributing to the adverse side‐effects of general chemotherapy.We have found that zebrafish T‐ALL cells acquired amplification and high expression of the Protein Tyrosine Phosphatase 4A3 (PRL3) concurrent with evolution of enhanced relapse potential in a transplantation screen involving over 6,000 animals. Further, approximately 50% of human T‐ALL patients have high PRL3 expression. PRL3 has not been associated with leukemia onset or progression, but here we show overexpression of PRL3 leads to increased T‐ALL onset and aggressiveness in an in vivo transgenic zebrafish T‐ALL model. Small molecule inhibitors of PRL3 significantly reduced viability of established cultures of human T‐ALL cells in vitro. Based on these data, we hypothesize that PRL3 plays an important role in T‐ALL cell survival at all stages of leukemia progression. We are currently using fluorescent and confocal microscopy in zebrafish over‐expressing PRL3 to determine the cellular mechanisms by which PRL3 enhances leukemia onset. We are also generating PRL3 knockout lines using a CRISPR‐Cas9 for similar studies. Finally, we are treating zebrafish bearing T‐ALL with two specific, research‐grade PRL inhibitors to determine if blocking PRL3 phosphatase activity prevents leukemia onset and relapse. We have also identified several FDA‐approved, general phosphatase inhibitors that have potent anti‐PRL activity and are capable of killing ALL cells in vitro. Current work is focused on screening these inhibitors in vivo in our zebrafish models.We conclude that PRL3 is a novel gene that may be important for T‐ALL onset and progression. As a phosphatase, it is a unique druggable target. Future directions will focus on identifying the molecular mechanisms by which PRL3 drives leukemia progression, and moving top drug hits from our zebrafish screens into pre‐clinical testing in patient derived xenografts models in mice. We hope that our findings may lead to eventual clinical trials as alternatives to the traditional cytotoxic chemotherapy offered to pediatric T‐ALL patients now.Support or Funding InformationNCI 4R00CA181500NIGMS P30GM110787The V Foundation for Cancer Research