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

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

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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.

Original languageEnglish (US)
Pages (from-to)1595-1603
Number of pages9
JournalJournal of Experimental Medicine
Volume208
Issue number18
DOIs
StatePublished - Aug 1 2011

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Gutierrez, A., Grebliunaite, R., Feng, H., Kozakewich, E., Zhu, S., Guo, F., Payne, E., Mansour, M., Dahlberg, S. E., Neuberg, D. S., den Hertog, J., Prochownik, E. V., Testa, J. R., Harris, M., Kanki, J. P., & 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(18), 1595-1603. https://doi.org/10.1084/jem.20101691