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Nat Med. 2016 Apr;22(4):379-87. doi: 10.1038/nm.4062. Epub 2016 Mar 14.

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

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  • 1Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
  • 2Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy.
  • 3Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
  • 4Department of Immunology, University of Ulm, Ulm, Germany.
  • 5Abteilung Hämatologie-Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany.
  • 6Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
  • 7Department of Molecular and Medical Pharmacology, University of California, Los Angeles (UCLA), Los Angeles, California, USA.


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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