Gene sets identified with oncogene cooperativity analysis regulate in vivo growth and survival of leukemia stem cells.
Cell Stem Cell, 2012/9/07;11(3):359-72.
Ashton JM[1], Balys M, Neering SJ, Hassane DC, Cowley G, Root DE, Miller PG, Ebert BL, McMurray HR, Land H, Jordan CT
Affiliations
PMID: 22863534DOI: 10.1016/j.stem.2012.05.024
Impact factor: 25.269
Abstract
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.
MeSH terms
Animals; Benzothiazoles; Blast Crisis; Cell Death; Cell Line, Tumor; Cell Proliferation; Cell Survival; Gene Expression Regulation, Leukemic; Humans; Leukemia; Mice; Mice, Inbred C57BL; Neoplastic Stem Cells; Oncogenes; Serpins; Tyrphostins
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