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

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

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

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.

Original languageEnglish
Pages (from-to)379-387
Number of pages9
JournalNature Medicine
Volume22
Issue number4
DOIs
StatePublished - 1 Apr 2016
Externally publishedYes

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