The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia

Abstract

The tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates phosphatidylinositol 3-kinase (PI3K)-AKT signaling and is often inactivated by mutations (including deletions) in a variety of cancer types, including T-cell acute lymphoblastic leukemia. Here we review mutation-associated mechanisms that inactivate PTEN together with other molecular mechanisms that activate AKT and contribute to T-cell leukemogenesis. In addition, we discuss how Pten mutations in mouse models affect the efficacy of gamma-secretase inhibitors to block NOTCH1 signaling through activation of AKT. Based on these models and on observations in primary diagnostic samples from patients with T-cell acute lymphoblastic leukemia, we speculate that PTEN-deficient cells employ an intrinsic homeostatic mechanism in which PI3K-AKT signaling is dampened over time. As a result of this reduced PI3K-AKT signaling, the level of AKT activation may be insufficient to compensate for NOTCH1 inhibition, resulting in responsiveness to gamma-secretase inhibitors. On the other hand, de novo acquired PTEN-inactivating events in NOTCH1-dependent leukemia could result in temporary, strong activation of PI3K-AKT signaling, increased glycolysis and glutaminolysis, and consequently gamma-secretase inhibitor resistance. Due to the central role of PTEN-AKT signaling and in the resistance to NOTCH1 inhibition, AKT inhibitors may be a promising addition to current treatment protocols for T-cell acute lymphoblastic leukemia.

Figure 1.

Schematic representation of the human PTEN gene located on chromosome 10q23. The PTEN gene contains nine exons, and the PTEN protein contains several functional domains, including a phosphatase domain (dark gray) and a C2 lipid-binding domain (light gray). The positions of nonsense insertion and deletion mutations are indicated by closed triangles, and missense mutations are indicated by open triangles. Microdeletions and deletions in the PTEN gene are shown below the exons. The number of patients with each mutation/deletion in our cohort of T-ALL patients is indicated.^,

Figure 2.

Schematic overview of the upstream and downstream effectors of PTEN and associated molecular mechanisms that can activate AKT and lead to GSI resistance. (A) PTEN-PI3K-AKT mutations. (B) NOTCH mutations and AKT activation. (C) MYC signaling and AKT activation. (D) IL7R/IGF1R signaling and AKT activation. The molecules with activating and inactivating mutations are indicated in dark gray and light gray, respectively. Dashed lines/arrows represent processes that contribute to cellular GSI sensitivity, and that are frequently inactivated by inactivating mutations/rearrangements in PTEN or FBXW7. Solid lines/arrows represent GSI resistance mechanisms.