Unique and Paradoxical Functions of the Tumor Suppressor PTEN

Phosphatase and tensin homolog (PTEN) is a potent tumor suppressor and plays an important role in regulating the phosphatidylinositol-3-kinase (PI3K) and protein kinase B (AKT) signaling pathway. The development of pre-B cells is tightly controlled and depends on a fine balance of PI3K-AKT activity. A loss of signaling or hyper-activation of the pathway both lead to cell death, whereas an intermediate level of activity allows pre-B cells to pass a tolerance checkpoint that is monitored by PTEN. Point mutations and deletions in PTEN are common in cancer, including hematological malignancies of the T cell lineage and mature B cell lymphomas, implying a tumor suppressor function. To investigate the role of PTEN in immature B cell cancer, Dr. Seyedmehdi Shojaee and colleagues generated mouse models of pre-B acute lymphoblastic leukemia (ALL) driven by the oncogenes BCR-ABL1 or NRAS^G12D. Cre-mediated inducible deletion of one or both of the loxP-flanked pten alleles in these mice surprisingly prevented malignant transformation and also led to the death of established leukemia cells, indicating that PTEN is required for both the initiation and maintenance of pre-B ALL in vivo. Consistent with these findings, there is no hyper-methylation of the PTEN promoter in pre-B ALL patients, resulting in higher levels of PTEN protein and a poor prognosis.

These paradoxical findings prompted reevaluation of genomic data from cancer patients, which confirmed the presence of PTEN mutations in solid tumors and blood cancers, consistent with a tumor suppressor role. However, no point mutations or deletions of PTEN were found in 925 cases of pre-B ALL, and activating mutations in agonists of the PI3K-AKT pathway were also not present, which supports the experimental mouse model evidence of Dr. Shojaee and colleagues. These data suggest that PTEN may have a fundamentally different function in pre-B ALL than in other hematopoietic malignancies. To elucidate the molecular mechanisms underlying the dependency of pre-B ALL on the presence of PTEN, the researchers used their mouse models to show that deletion of the PTEN gene increased phosphorylation of AKT and the activity of the PI3K-AKT cascade. Additional sophisticated gene manipulation experiments demonstrated that the hyperactive PI3K-AKT pathway triggered a checkpoint to eliminate the leukemic cells in a manner similar to the removal of auto-reactive B cells. They further showed that the pro-survival function of PTEN is unique to the B-cell lineage and that myeloid cells did not show this dependency.

These findings prompted an investigation of PTEN as a therapeutic target. Using shRNA technology, researchers knocked down PTEN in cells from four patients with pre-B ALL, which caused the death of the leukemic cells, with no effect on the viability of myeloid leukemia cell lines. Similar results were obtained when they performed pre-clinical testing of SF1670, a small-molecule inhibitor of PTEN. However, since PTEN is an important regulator of several cellular processes, as well as a tumor suppressor in other types of cells, adverse effects may be problematic and would require extensive further evaluation prior to the use of PTEN inhibitors in the clinic.