Regulation and Function of the Phosphatase PHLPP2 in Leukemia

Abstract

PHLPP2, a member of the PHLPP phosphatase family, which targets oncogenic kinases, has been actively investigated as a tumor suppressor in solid tumors. Little was known, however, regarding its regulation and function in hematological malignancies. The first half of this dissertation describes a novel miR-17~92-based mechanism for repression of PHLPP2 protein expression in late differentiation stage acute myeloid leukemia (AML) subtypes. ATRA (all-trans retinoic acid), a drug used for terminally differentiating AML subtypes, was able to induce PHLPP2 protein levels and phosphatase activity significantly by suppressing miR-17-92 expression. The effect of ATRA on miR-17~92 expression was mediated through its target, transcription factor C/EBP, which interacts with the intronic promoter of the miR-17~92 gene cluster to inhibit its transactivation. The second half of this dissertation provides evidence for a novel metabolic function for PHLPP2 and describes the first identification of the energy sensing kinase, AMPK, as a unique PHLPP2 substrate. PHLPP2 could dephosphorylate phospho-AMPK (T172) both intracellularly and in vitro. PHLPP2 silencing protected Jurkat T-ALL cells from an apoptotic response to low glucose-induced metabolic stress through activation of AMPK signaling. The pro-survival effect of PHLPP2 knockdown under metabolic stress is likely mediated through AMPK-activated fatty acid oxidation. PHLPP2 regulates AMPK phosphorylation in a variety of tumor types and is the first specific AMPK phosphatase to be identified. These studies on PHLPP2 expression and function expand current knowledge and understanding of the role of PHLPP phosphatases in cancer, and particularly in leukemia. In light of the pivotal role played by AMPK in a number of metabolic diseases, the PHLPP2/AMPK axis is also expected to provide new insights into therapies targeting these diseases.