TY - JOUR
T1 - Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia
AU - Gutierrez, Alejandro
AU - Grebliunaite, Ruta
AU - Feng, Hui
AU - Kozakewich, Elena
AU - Zhu, Shizhen
AU - Guo, Feng
AU - Payne, Elspeth
AU - Mansour, Marc
AU - Dahlberg, Suzanne E.
AU - Neuberg, Donna S.
AU - den Hertog, Jeroen
AU - Prochownik, Edward V.
AU - Testa, Joseph R.
AU - Harris, Marian
AU - Kanki, John P.
AU - Look, A. Thomas
PY - 2011/8/1
Y1 - 2011/8/1
N2 - 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.
AB - 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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UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000293441500005&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1084/jem.20101691
DO - 10.1084/jem.20101691
M3 - Article
C2 - 21727187
SN - 0022-1007
VL - 208
SP - 1595
EP - 1603
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 18
ER -