title: PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability.
abstract: Mutations in the phosphatase and tensin homolog (PTEN) gene leading to PTEN protein deletion and subsequent activation of the PI3K/Akt signaling pathway are common in cancer. Here we show that PTEN inactivation in human T cell acute lymphoblastic leukemia (T-ALL) cells is not always synonymous with PTEN gene lesions and diminished protein expression. Samples taken from patients with T-ALL at the time of diagnosis very frequently showed constitutive hyperactivation of the PI3K/Akt pathway. In contrast to immortalized cell lines, most primary T-ALL cells did not harbor PTEN gene alterations, displayed normal PTEN mRNA levels, and expressed higher PTEN protein levels than normal T cell precursors. However, PTEN overexpression was associated with decreased PTEN lipid phosphatase activity, resulting from casein kinase 2 (CK2) overexpression and hyperactivation. In addition, T-ALL cells had constitutively high levels of ROS, which can also downmodulate PTEN activity. Accordingly, both CK2 inhibitors and ROS scavengers restored PTEN activity and impaired PI3K/Akt signaling in T-ALL cells. Strikingly, inhibition of PI3K and/or CK2 promoted T-ALL cell death without affecting normal T cell precursors. Overall, our data indicate that T-ALL cells inactivate PTEN mostly in a nondeletional, posttranslational manner. Pharmacological manipulation of these mechanisms may open new avenues for T-ALL treatment.
authors.affiliation: Unidade de Biologia do Cancro, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Silva
authors.forename: J Andrés
authors.initials: JA
authors.lastname: Yunes
authors.forename: Bruno A
authors.initials: BA
authors.lastname: Cardoso
authors.forename: Leila R
authors.initials: LR
authors.lastname: Martins
authors.forename: Patrícia Y
authors.initials: PY
authors.lastname: Jotta
authors.forename: Miguel
authors.initials: M
authors.lastname: Abecasis
authors.forename: Alexandre E
authors.initials: AE
authors.lastname: Nowill
authors.forename: Nick R
authors.initials: NR
authors.lastname: Leslie
authors.forename: Angelo A
authors.initials: AA
authors.lastname: Cardoso
authors.forename: Joao T
authors.initials: JT
authors.lastname: Barata
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D006801:Humans; D008954:Models, Biological; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt