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

PTEN is a negative regulator of PI3K-AKT signaling and a potent tumor suppressor in many types of cancer. To test a tumor suppressive role of 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 su...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5178869/
https://www.ncbi.nlm.nih.gov/pubmed/26974310
http://dx.doi.org/10.1038/nm.4062
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author 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
author_facet 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
author_sort Shojaee, Seyedmehdi
collection PubMed
description PTEN is a negative regulator of PI3K-AKT signaling and a potent tumor suppressor in many types of cancer. To test a tumor suppressive role of 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 AKT hyperactivation, p53 checkpoint activation and cell death. Loss of PTEN function in pre-B ALL cells was functionally equivalent to acute activation of autoreactive pre-BCR signaling, which engaged a deletional checkpoint for removal of autoreactive B cells. We propose that targeted inhibition of PTEN and hyperactivation of AKT triggers a checkpoint for elimination of autoreactive B cells and represents a new strategy to overcome drug-resistance in human ALL.
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spelling pubmed-51788692016-12-22 PTEN opposes negative selection and enables oncogenic transformation of pre-B cells 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 Nat Med Article PTEN is a negative regulator of PI3K-AKT signaling and a potent tumor suppressor in many types of cancer. To test a tumor suppressive role of 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 AKT hyperactivation, p53 checkpoint activation and cell death. Loss of PTEN function in pre-B ALL cells was functionally equivalent to acute activation of autoreactive pre-BCR signaling, which engaged a deletional checkpoint for removal of autoreactive B cells. We propose that targeted inhibition of PTEN and hyperactivation of AKT triggers a checkpoint for elimination of autoreactive B cells and represents a new strategy to overcome drug-resistance in human ALL. 2016-03-14 2016-04 /pmc/articles/PMC5178869/ /pubmed/26974310 http://dx.doi.org/10.1038/nm.4062 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
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
PTEN opposes negative selection and enables oncogenic transformation of pre-B cells
title PTEN opposes negative selection and enables oncogenic transformation of pre-B cells
title_full PTEN opposes negative selection and enables oncogenic transformation of pre-B cells
title_fullStr PTEN opposes negative selection and enables oncogenic transformation of pre-B cells
title_full_unstemmed PTEN opposes negative selection and enables oncogenic transformation of pre-B cells
title_short PTEN opposes negative selection and enables oncogenic transformation of pre-B cells
title_sort pten opposes negative selection and enables oncogenic transformation of pre-b cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5178869/
https://www.ncbi.nlm.nih.gov/pubmed/26974310
http://dx.doi.org/10.1038/nm.4062
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