PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Mutations in the phosphatase and tensin homolog (PTEN) gene are common drivers of cancer, leading to PI3K/Akt pathway activation.
• PTEN protein deletion and subsequent PI3K/Akt pathway activation are frequently observed in various cancers, including T cell acute lymphoblastic leukemia (T-ALL).

Purpose of the Study:

• To investigate the mechanisms of PTEN inactivation in primary T-ALL cells.
• To explore potential therapeutic strategies targeting PTEN inactivation pathways in T-ALL.

Main Methods:

• Analysis of PTEN gene lesions, mRNA, and protein levels in primary T-ALL patient samples.
• Assessment of PTEN lipid phosphatase activity in relation to casein kinase 2 (CK2) and reactive oxygen species (ROS) levels.
• Inhibition of CK2 and ROS in T-ALL cells and evaluation of effects on PTEN activity, PI3K/Akt signaling, and cell viability.

Main Results:

• Most primary T-ALL cells exhibited PTEN inactivation without PTEN gene alterations, showing normal mRNA but increased protein levels.
• Increased PTEN protein levels correlated with decreased lipid phosphatase activity due to CK2 and ROS hyperactivation.
• CK2 inhibitors and ROS scavengers restored PTEN activity, inhibited PI3K/Akt signaling, and induced T-ALL cell death.

Conclusions:

• PTEN inactivation in T-ALL predominantly occurs through post-translational modifications rather than gene deletions.
• Targeting CK2 and ROS pathways represents a promising therapeutic approach for T-ALL, selectively eliminating cancer cells.