期刊
CANCER CELL
卷 25, 期 3, 页码 366-378出版社
CELL PRESS
DOI: 10.1016/j.ccr.2014.01.032
关键词
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资金
- Alex Lemonade Stand Foundation
- Leukemia and Lymphoma Society
- Massachusetts General Hospital Toteson Fund for Medical Discovery Postdoctoral Fellowship
- National Institutes of Health (NIH) [1K99CA181500-01]
- NIH [F32DK098875, R01-GM081533, U01-HG005725]
- American Cancer Society
- Leukemia Research Foundation
- Harvard Stem Cell Institute
- MGH Goodman Fellowship
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.
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