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

  • Author(s): 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
  • et al.

Published Web Location

https://doi.org/10.1038/nm.4062
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.

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