Gene sets identified with oncogene cooperativity analysis regulate in vivo growth and survival of leukemia stem cells

Cell Stem Cell. 2012 Sep 7;11(3):359-72. doi: 10.1016/j.stem.2012.05.024. Epub 2012 Aug 2.


Leukemia stem cells (LSCs) represent a biologically distinct subpopulation of myeloid leukemias, with reduced cell cycle activity and increased resistance to therapeutic challenge. To better characterize key properties of LSCs, we employed a strategy based on identification of genes synergistically dysregulated by cooperating oncogenes. We hypothesized that such genes, termed "cooperation response genes" (CRGs), would represent regulators of LSC growth and survival. Using both a primary mouse model and human leukemia specimens, we show that CRGs comprise genes previously undescribed in leukemia pathogenesis in which multiple pathways modulate the biology of LSCs. In addition, our findings demonstrate that the CRG expression profile can be used as a drug discovery tool for identification of compounds that selectively target the LSC population. We conclude that CRG-based analyses provide a powerful means to characterize the basic biology of LSCs as well as to identify improved methods for therapeutic targeting.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Benzothiazoles / pharmacology
  • Blast Crisis / genetics
  • Blast Crisis / pathology
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Gene Expression Regulation, Leukemic / drug effects
  • Humans
  • Leukemia / genetics*
  • Leukemia / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology*
  • Oncogenes / genetics*
  • Serpins / metabolism
  • Tyrphostins / pharmacology


  • Benzothiazoles
  • Serpins
  • Tyrphostins
  • tyrphostin AG825

Associated data

  • GEO/GSE37907