title: Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia.
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.
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. alejandro_gutierrez@dfci.harvard.edu
authors: Alejandro
authors: A
authors: Gutierrez
authors: Ruta
authors: R
authors: Grebliunaite
authors: Hui
authors: H
authors: Feng
authors: Elena
authors: E
authors: Kozakewich
authors: Shizhen
authors: S
authors: Zhu
authors: Feng
authors: F
authors: Guo
authors: Elspeth
authors: E
authors: Payne
authors: Marc
authors: M
authors: Mansour
authors: Suzanne E
authors: SE
authors: Dahlberg
authors: Donna S
authors: DS
authors: Neuberg
authors: Jeroen
authors: J
authors: den Hertog
authors: Edward V
authors: EV
authors: Prochownik
authors: Joseph R
authors: JR
authors: Testa
authors: Marian
authors: M
authors: Harris
authors: John P
authors: JP
authors: Kanki
authors: A Thomas
authors: AT
authors: Look
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D016616:Cryoultramicrotomy; D017931:DNA Primers / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D013629:Tamoxifen / Q000031:analogs & derivatives; D015027:Zebrafish
chemical_list: D017931:DNA Primers; D016271:Proto-Oncogene Proteins c-myc; D013629:Tamoxifen; C016601:afimoxifene; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase