Clonal Evolution Enhances Leukemia-Propagating Cell Frequency in T Cell Acute Lymphoblastic Leukemia Through Akt/mTORC1 Pathway Activation

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

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.

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
  • Mechanistic Target of Rapamycin Complex 1
  • 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

Substances

  • Antineoplastic Agents, Hormonal
  • Heterocyclic Compounds, 3-Ring
  • MK 2206
  • Multiprotein Complexes
  • Proto-Oncogene Proteins c-myc
  • Dexamethasone
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt

Associated data

  • GENBANK/GSE54482