Title | PTEN opposes negative selection and enables oncogenic transformation of pre-B cells. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | 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, and Müschen Markus |
Journal | Nat Med |
Volume | 22 |
Issue | 4 |
Pagination | 379-87 |
Date Published | 2016 Apr |
ISSN | 1546-170X |
Keywords | Animals, 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> |
DOI | 10.1038/nm.4062 |
Alternate Journal | Nat Med |
PubMed ID | 26974310 |
PubMed Central ID | PMC5178869 |
Grant List | UL1TR000124 / 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 |