PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability
Ana Silva, … , Angelo A. Cardoso, Joao T. Barata
Ana Silva, … , Angelo A. Cardoso, Joao T. Barata
Published October 1, 2008
Citation Information: J Clin Invest. 2008;118(11):3762-3774. https://doi.org/10.1172/JCI34616.
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Research Article Hematology

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

Ana Silva, J. Andrés Yunes, Bruno A. Cardoso, Leila R. Martins, Patrícia Y. Jotta, Miguel Abecasis, Alexandre E. Nowill, Nick R. Leslie, Angelo A. Cardoso, Joao T. Barata

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Figure 6

Cooperative effects of combinatorial treatment of T-ALL cells with pharmacological antagonists of PI3K, CK2, and ROS.

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Cooperative effects of combinatorial treatment of T-ALL cells with pharm...
(A and B) Inhibition of CK2 and ROS scavenging cooperate in inducing T-ALL cell death. TAIL7 cells were cultured with the indicated concentrations of TBB and β-ME (A), TBB and NAC (B), or their combination, and viability was assessed at 72 h. (C–F) Inhibition of PI3K signaling cooperates with inhibition of CK2 and ROS scavenging in inducing T-ALL cell death. TAIL7 cells were cultured with the indicated concentrations of LY294002 and TBB (C), LY294002 and DRB (D), LY294002 and β-ME (E), LY294002 and NAC (F), or their combination, and viability was assessed at 72 h. Percent viability relative to untreated control (vehicle alone) is indicated for each condition. Similar results were obtained using HPB-ALL and primary T-ALL cells (Supplemental Figures 17 and 18). Data are mean ± SEM.