Pten Mediates Myc Oncogene Dependence in a Conditional Zebrafish Model of T Cell Acute Lymphoblastic Leukemia

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2011 Jul 6

PMID 21727187

Citations 61

Authors

Alejandro Gutierrez

Ruta Grebliunaite

Hui Feng

Elena Kozakewich

Shizhen Zhu

Feng Guo

Elspeth Payne

Marc Mansour

Suzanne E Dahlberg

Donna S Neuberg

Jeroen den Hertog

Edward V Prochownik

Joseph R Testa

Marian Harris

John P Kanki

A Thomas Look

Affiliations

Soon will be listed here.

Abstract

The MYC oncogenic transcription factor is overexpressed in most human cases of T cell acute lymphoblastic leukemia (T-ALL), often downstream of mutational NOTCH1 activation. Genetic alterations in the PTEN-PI3K-AKT pathway are also common in T-ALL. We generated a conditional zebrafish model of T-ALL in which 4-hydroxytamoxifen (4HT) treatment induces MYC activation and disease, and withdrawal of 4HT results in T-ALL apoptosis and tumor regression. However, we found that loss-of-function mutations in zebrafish pten genes, or expression of a constitutively active Akt2 transgene, rendered tumors independent of the MYC oncogene and promoted disease progression after 4HT withdrawal. Moreover, MYC suppresses pten mRNA levels, suggesting that Akt pathway activation downstream of MYC promotes tumor progression. Our findings indicate that Akt pathway activation is sufficient for tumor maintenance in this model, even after loss of survival signals driven by the MYC oncogene.

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