Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 208, Issue 8, Pages 1595-1603Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20101691
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Funding
- National Institutes of Health [NCI 5P01CA68484, NCI 1K08CA133103]
- William Lawrence Foundation
- National Cancer Institute (NCI)/National Institutes of Health [K99CA134743, P30 CA-06927]
- Commonwealth of Pennsylvania
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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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