- Shojaee, Seyedmehdi;
- Chan, Lai N;
- Buchner, Maike;
- Cazzaniga, Valeria;
- Cosgun, Kadriye Nehir;
- Geng, Huimin;
- Qiu, Yi Hua;
- von Minden, Marcus Dühren;
- Ernst, Thomas;
- Hochhaus, Andreas;
- Cazzaniga, Giovanni;
- Melnick, Ari;
- Kornblau, Steven M;
- Graeber, Thomas G;
- Wu, Hong;
- Jumaa, Hassan;
- Müschen, Markus
Phosphatase and tensin homolog (PTEN) is a negative regulator of the phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) signaling pathway and a potent tumor suppressor in many types of cancer. To test a tumor suppressive role for PTEN in pre-B acute lymphoblastic leukemia (ALL), we induced Cre-mediated deletion of Pten in mouse models of pre-B ALL. In contrast to its role as a tumor suppressor in other cancers, loss of one or both alleles of Pten caused rapid cell death of pre-B ALL cells and was sufficient to clear transplant recipient mice of leukemia. Small-molecule inhibition of PTEN in human pre-B ALL cells resulted in hyperactivation of AKT, activation of the p53 tumor suppressor cell cycle checkpoint and cell death. Loss of PTEN function in pre-B ALL cells was functionally equivalent to acute activation of autoreactive pre-B cell receptor signaling, which engaged a deletional checkpoint for the removal of autoreactive B cells. We propose that targeted inhibition of PTEN and hyperactivation of AKT triggers a checkpoint for the elimination of autoreactive B cells and represents a new strategy to overcome drug resistance in human ALL.