title: 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.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Seyedmehdi
authors.initials: S
authors.lastname: Shojaee
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Lai N
authors.initials: LN
authors.lastname: Chan
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Maike
authors.initials: M
authors.lastname: Buchner
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.|Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Cazzaniga
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Kadriye Nehir
authors.initials: KN
authors.lastname: Cosgun
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Huimin
authors.initials: H
authors.lastname: Geng
authors.affiliation: Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Yi Hua
authors.initials: YH
authors.lastname: Qiu
authors.affiliation: Department of Immunology, University of Ulm, Ulm, Germany.
authors.forename: Marcus Dühren
authors.initials: MD
authors.lastname: von Minden
authors.affiliation: Abteilung Hämatologie-Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ernst
authors.affiliation: Abteilung Hämatologie-Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.affiliation: Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cazzaniga
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.affiliation: Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles (UCLA), Los Angeles, California, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Graeber
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles (UCLA), Los Angeles, California, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Immunology, University of Ulm, Ulm, Germany.
authors.forename: Hassan
authors.initials: H
authors.lastname: Jumaa
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D054420:Pre-B Cell Receptors / Q000235:genetics; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D054420:Pre-B Cell Receptors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse