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Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia

Gutierrez, A. and Grebliunaite, R. and Feng, H. and Kozakewich, E. and Zhu, S. and Guo, F. and Payne, E. and Mansour, M. and Dahlberg, S. E. and Neuberg, D. S. and Hertog den, J. and Prochownik, E. V. and Testa, J. R. and Harris, M. and Kanki, J. P. and Look, A. T. (2011) Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia. Journal of Experimental Medicine, 208, 1595-603. ISSN 0022-1007.

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Official URL: http://dx.doi.org/10.1084/jem.20101691

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. [KEYWORDS: Animals, Animals, Genetically Modified, Apoptosis/genetics, Blotting, Western, Cryoultramicrotomy, DNA Primers/genetics, Gene Expression Regulation, Neoplastic/ genetics, Immunohistochemistry, In Situ Hybridization, PTEN Phosphohydrolase/genetics/ metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/ metabolism, Proto-Oncogene Proteins c-akt/ metabolism, Proto-Oncogene Proteins c-myc/ metabolism, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction/ genetics, T

Item Type:Article
Institutes:Hubrecht Instituut
ID Code:12614
Deposited On:07 Sep 2012 13:23
Last Modified:19 Sep 2012 16:37

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