PML Controls PTEN Localization and Function in APL through a Novel Deubiquitination Pathway

PML was discovered as a gene frequently involved in the t(15:17) translocation of acute promyelocytic leukemia (APL). Since then, consequences of PML-loss of function in APL and other solid tumors have been extensively studied. Numerous pathways influenced by this tumor suppressor, including the PI3K pathway, have been identified but their importance for the pathogenesis APL is still unclear. We have now discovered that PTEN, the main tumor suppressor opposing PI3K signaling, is aberrantly delocalized to the cytoplasm in APL, but not in AML. Moreover, we show that drugs such as arsenic trioxide and retinoic acid, currently used for the treatment of APL and known to target the oncogenic PML-RARalpha fusion protein, rescue the nuclear localization of PTEN. This discovery has critical biological implications since nuclear localization of PTEN is central to its tumor suppressive activity. Utilizing an APL cell line, genetically engineered cells and transgenic mice, we have delineated the mechanism by which PML sustains nuclear PTEN. PML opposes the activity of a novel PTEN-deubiquitinating enzyme, HAUSP, towards PTEN through a framework involving the adaptor protein DAXX (death domain-associated protein). We demonstrate that PML-RARalpha translocation results in overactive HAUSP and as a consequence, nuclear-excluded PTEN. In support of this notion, we show that HAUSP is overexpressed in human cancer, (e.g. in prostate cancer) which is in turn associated with a nuclear exclusion phenotype of PTEN. Overall our results describe a novel role for PML in the maintenance of PTEN function that is perturbed by oncogenic cues in human leukemia and solid tumors. Significantly, our findings open new avenues for the design of targeted therapies focused on potentiating the activity of the PML-PTEN tumor suppressive network.