PTEN opposes negative selection and enables oncogenic transformation of pre-B cells.

Abstract

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.

• Authors: Seyedmehdi Shojaee, Lai N Chan, Maike Buchner, Valeria Cazzaniga, Kadriye Nehir Cosgun, Huimin Geng, Yi Hua Qiu, Marcus Dühren von Minden, Thomas Ernst, Andreas Hochhaus, Giovanni Cazzaniga, Ari Melnick, Steven M Kornblau, Thomas G Graeber, Hong Wu, Hassan Jumaa, Markus Müschen
• Journal: Nature medicine (Nat Med) Vol. 22 Issue 4 Pg. 379-87 (Apr 2016) ISSN: 1546-170X [Electronic] United States
• PMID: 26974310 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Pre-B Cell Receptors
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• PTEN Phosphohydrolase
• Pten protein, mouse

Topics

• Animals
• B-Lymphocytes (metabolism, pathology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (genetics)
• Humans
• Mice
• Mice, Transgenic
• PTEN Phosphohydrolase (genetics)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Pre-B Cell Receptors (genetics)
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (genetics, pathology)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Signal Transduction