title: Gene sets identified with oncogene cooperativity analysis regulate in vivo growth and survival of leukemia stem cells.
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.
authors.affiliation: James P. Wilmot Cancer Center, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY 14642, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Ashton
authors.forename: Marlene
authors.initials: M
authors.lastname: Balys
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Neering
authors.forename: Duane C
authors.initials: DC
authors.lastname: Hassane
authors.forename: Glenn
authors.initials: G
authors.lastname: Cowley
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.forename: Peter G
authors.initials: PG
authors.lastname: Miller
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
authors.forename: Helene R
authors.initials: HR
authors.lastname: McMurray
authors.forename: Hartmut
authors.initials: H
authors.lastname: Land
authors.forename: Craig T
authors.initials: CT
authors.lastname: Jordan
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology; D001752:Blast Crisis / Q000235:genetics / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009857:Oncogenes / Q000235:genetics*; D015843:Serpins / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D052160:Benzothiazoles; D015843:Serpins; D020032:Tyrphostins; C098214:tyrphostin AG825