TitlePTEN opposes negative selection and enables oncogenic transformation of pre-B cells.
Publication TypeJournal Article
Year of Publication2016
AuthorsShojaee, 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, and Müschen Markus
JournalNat Med
Volume22
Issue4
Pagination379-87
Date Published2016 Apr
ISSN1546-170X
KeywordsAnimals, B-Lymphocytes, Cell Line, Tumor, Drug Resistance, Neoplasm, Humans, Mice, Mice, Transgenic, Phosphatidylinositol 3-Kinases, Pre-B Cell Receptors, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Signal Transduction
Abstract

<p>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. </p>

DOI10.1038/nm.4062
Alternate JournalNat Med
PubMed ID26974310
PubMed Central IDPMC5178869
Grant ListUL1TR000124 / TR / NCATS NIH HHS / United States
R01 CA213138 / CA / NCI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
R01 CA157644 / CA / NCI NIH HHS / United States
R01 CA172558 / CA / NCI NIH HHS / United States
R01CA137060 / CA / NCI NIH HHS / United States
R01 CA169458 / CA / NCI NIH HHS / United States
R35 CA197628 / CA / NCI NIH HHS / United States
R01CA169458 / CA / NCI NIH HHS / United States
R01 CA139032 / CA / NCI NIH HHS / United States
R01CA157644 / CA / NCI NIH HHS / United States
R01CA172558 / CA / NCI NIH HHS / United States
/ / Wellcome Trust / United Kingdom
R01CA139032 / CA / NCI NIH HHS / United States
R01 CA137060 / CA / NCI NIH HHS / United States