PUBLICATION
Clonal evolution enhances leukemia-propagating cell frequency in T cell acute lymphoblastic leukemia through Akt/mTORC1 pathway activation
- Authors
- Blackburn, J.S., Liu, S., Wilder, J.L., Dobrinski, K.P., Lobbardi, R., Moore, F.E., Martinez, S.A., Chen, E.Y., Lee, C., Langenau, D.M.
- ID
- ZDB-PUB-140513-379
- Date
- 2014
- Source
- Cancer Cell 25: 366-78 (Journal)
- Registered Authors
- Dobrinski, Kim P., Langenau, David, Lee, Charles
- Keywords
- none
- Datasets
- GEO:GSE54482
- MeSH Terms
-
- Genetic Variation
- Animals, Genetically Modified
- Clonal Evolution/genetics*
- Proto-Oncogene Proteins c-myc/metabolism*
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics
- PubMed
- 24613413 Full text @ Cancer Cell
Abstract
Clonal evolution and intratumoral heterogeneity drive cancer progression through unknown molecular mechanisms. To address this issue, functional differences between single T cell acute lymphoblastic leukemia (T-ALL) clones were assessed using a zebrafish transgenic model. Functional variation was observed within individual clones, with a minority of clones enhancing growth rate and leukemia-propagating potential with time. Akt pathway activation was acquired in a subset of these evolved clones, which increased the number of leukemia-propagating cells through activating mTORC1, elevated growth rate likely by stabilizing the Myc protein, and rendered cells resistant to dexamethasone, which was reversed by combined treatment with an Akt inhibitor. Thus, T-ALL clones spontaneously and continuously evolve to drive leukemia progression even in the absence of therapy-induced selection.
Genes / Markers
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Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
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