PUBLICATION
Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia
- Authors
- Gutierrez, A., Grebliunaite, R., Feng, H., Kozakewich, E., Zhu, S., Guo, F., Payne, E., Mansour, M., Dahlberg, S.E., Neuberg, D.S., Hertog, J.D., Prochownik, E.V., Testa, J.R., Harris, M., Kanki, J.P., and Look, A.T.
- ID
- ZDB-PUB-110713-19
- Date
- 2011
- Source
- The Journal of experimental medicine 208(8): 1595-603 (Journal)
- Registered Authors
- Feng, Hui, Gutierrez, Alejandro, Kanki, John, Look, A. Thomas, Mansour, Marc, Payne, Elspeth M. (Beth), Zhu, Shizhen
- Keywords
- none
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Apoptosis/genetics
- Blotting, Western
- Cryoultramicrotomy
- DNA Primers/genetics
- Gene Expression Regulation, Neoplastic/genetics*
- Immunohistochemistry
- In Situ Hybridization
- PTEN Phosphohydrolase/genetics
- PTEN Phosphohydrolase/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*
- Tamoxifen/analogs & derivatives
- Zebrafish
- PubMed
- 21727187 Full text @ J. Exp. Med.
Citation
Gutierrez, A., Grebliunaite, R., Feng, H., Kozakewich, E., Zhu, S., Guo, F., Payne, E., Mansour, M., Dahlberg, S.E., Neuberg, D.S., Hertog, J.D., Prochownik, E.V., Testa, J.R., Harris, M., Kanki, J.P., and Look, A.T. (2011) Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia. The Journal of experimental medicine. 208(8):1595-603.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping