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

Jessica S. Blackburn, Sali Liu, Jayme L. Wilder, Kimberly P. Dobrinski, Riadh Lobbardi, Finola E. Moore, Sarah A. Martinez, Eleanorc A. Chen, Charles Lee, David M. Langenau

Research output: Contribution to journalArticlepeer-review

92 Scopus citations


Clonal evolution and intratumoral heterogeneity drive cancer progression through unknown molecular mechanisms. To address this issue, functional differences between single Tcell 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.

Original languageEnglish
Pages (from-to)366-378
Number of pages13
JournalCancer Cell
Issue number3
StatePublished - Mar 17 2014

Bibliographical note

Funding Information:
We thank Dr. Ravi Mylvaganam for expert advice and assistance with FACS and Eric Stone and Marcellino Pena for excellent zebrafish husbandry. We thank Dr. Alejandro Gutierrez and Dr. Hui Feng for reagents and technical advice and Dr. Donna Neuberg for assistance with statistical analyses. J.S.B. is supported by the Alex Lemonade Stand Foundation Young Investigator Award, the Leukemia and Lymphoma Society Special Fellow Award, the Massachusetts General Hospital Toteson Fund for Medical Discovery Postdoctoral Fellowship, and National Institutes of Health (NIH) grant 1K99CA181500-01. F.E.M. is supported by NIH grant F32DK098875. C.L. received support from NIH grants R01-GM081533 and U01-HG005725. D.M.L. received funding for this project from the American Cancer Society, the Leukemia Research Foundation, the Harvard Stem Cell Institute, the MGH Goodman Fellowship, and the Alex Lemonade Stand Foundation Innovation Grant.

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research


Dive into the research topics of 'Clonal evolution enhances leukemia-propagating cell frequency in T cell acute lymphoblastic leukemia through Akt/mTORC1 pathway activation'. Together they form a unique fingerprint.

Cite this