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Cancer Cell. 2014 Mar 17;25(3):366-78. doi: 10.1016/j.ccr.2014.01.032. Epub 2014 Mar 6.

Clonal evolution enhances leukemia-propagating cell frequency in T cell acute lymphoblastic leukemia through Akt/mTORC1 pathway activation.

Author information

1
Department of Pathology, Regenerative Medicine and Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Boston, MA 02138, USA.
2
Northwestern University, Chicago, IL 60208, USA.
3
Harvard Stem Cell Institute, Boston, MA 02138, USA.
4
Center for Integrative Medicine, University of South Florida, Tampa, FL 33620, USA.
5
Department of Pathology, Regenerative Medicine and Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA.
6
Department of Pathology, Regenerative Medicine and Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Boston, MA 02138, USA; Department of Pathology, University of Washington Medical Center, Seattle, WA 98195, USA.
7
The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030, USA; Department of Graduate Studies, Seoul National University School of Medicine, Seoul 110-744, South Korea.
8
Department of Pathology, Regenerative Medicine and Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Boston, MA 02138, USA. Electronic address: dlangenau@mgh.harvard.edu.

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.

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PMID:
24613413
PMCID:
PMC3992437
DOI:
10.1016/j.ccr.2014.01.032
[Indexed for MEDLINE]
Free PMC Article

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