| First Author | Shojaee S | Year | 2016 |
| Journal | Nat Med | Volume | 22 |
| Issue | 4 | Pages | 379-87 |
| PubMed ID | 26974310 | Mgi Jnum | J:234820 |
| Mgi Id | MGI:5790915 | Doi | 10.1038/nm.4062 |
| Citation | Shojaee S, et al. (2016) PTEN opposes negative selection and enables oncogenic transformation of pre-B cells. Nat Med 22(4):379-87 |
| abstractText | 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. |
