Gene Sets Identified with Oncogene Cooperativity Analysis Regulate In Vivo Growth and Survival of Leukemia Stem Cells
Menée sur des échantillons prélevés sur des patients atteints d'une leucémie et à l'aide d'un modèle murin, cette étude met en évidence des gènes impliqués dans la régulation de la croissance et de la survie des cellules souches leucémiques
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. º Downstream targets of cooperating oncogenes are identified in leukemia cells º Gene sets that regulate the in vivo behavior of leukemia stem cells are described º Genes modulating in vivo biology of leukemia stem cells are used for drug discovery Analysis of cooperative oncogenic interactions in a mouse model of acute leukemia reveal genes previously undescribed in leukemia pathogenesis. These genes were shown to modulate in vivo growth of leukemia cells and to represent targets for pharmacological inhibition.
http://linkinghub.elsevier.com/retrieve/pii/S1934590912003517 2012