ZFIN ID: ZDB-PUB-140513-379
Clonal evolution enhances leukemia-propagating cell frequency in T cell acute lymphoblastic leukemia through Akt/mTORC1 pathway activation
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.
Date: 2014
Source: Cancer Cell   25: 366-78 (Journal)
Registered Authors: Dobrinski, Kim P., Langenau, David, Lee, Charles
Keywords: none
Microarrays: GEO:GSE54482
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Antineoplastic Agents, Hormonal/pharmacology
  • Apoptosis/genetics
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic/genetics
  • Clonal Evolution/genetics*
  • Dexamethasone/pharmacology
  • Disease Progression
  • Drug Resistance, Neoplasm
  • Enzyme Activation
  • Genetic Variation
  • Heterocyclic Compounds, 3-Ring/pharmacology
  • Humans
  • Molecular Sequence Data
  • Multiprotein Complexes/metabolism*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism*
  • Proto-Oncogene Proteins c-akt/antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt/metabolism*
  • Proto-Oncogene Proteins c-myc/metabolism*
  • T-Lymphocytes/cytology
  • T-Lymphocytes/pathology
  • TOR Serine-Threonine Kinases/metabolism*
  • Zebrafish
PubMed: 24613413 Full text @ Cancer Cell
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.