Transcriptomics

Dataset Information

95

Leukemia stem cell-enriched population expresses self-renewal gene-expression signature [RNA-Seq]


ABSTRACT: Mutant RAS oncoproteins activate signaling molecules that drive oncogenesis in multiple human tumors including acute myelogenous leukemia (AML). However, the specific function of these pathways in AML is unclear. To elucidate the downstream functions of activated NRAS in AML, we employed a murine model of AML harboring Mll-AF9 and NRASG12V. We found that NRASG12V enforced leukemia self-renewal gene expression signatures and was required to maintain an MLL-AF9 and MYB-dependent gene expression program. In a multiplexed analysis of RAS-dependent signaling intermediates, the leukemia stem cell compartment was preferentially sensitive to RAS withdrawal. Use of RAS-pathway inhibitors showed that NRASG12V maintained leukemia self-renewal through mTOR and MEK pathway activation, implicating these pathways as potential targets for cancer stem cell-specific therapies. Primary leukemia cells harvested from spleens were sorted into immunophenotypic subpopulations (Mac-1High, Mac-1LowKit–Sca-1–, Mac-1LowKit+Sca-1–, and Mac-1LowKit+Sca-1+). RNA was extracted from this subpopulations of cells and submitted for RNA sequencing.

ORGANISM(S): Mus musculus  

SUBMITTER: Gary P Nolan  Miechaleen D Diers   Susan K Rathe   Aaron L Sarver   Rebecca S LaRue   Hanh T Nguyen   Karen Sachs   David A Largaespada   Sean C Bendall   Kevin M Shannon   Zohar Sachs   Ngoc A Ha   Nurul A Hassan   Ernesto Diaz-Flores    

PROVIDER: E-GEOD-63312 | ArrayExpress| 2014-11-28

SECONDARY ACCESSION(S): SRP049821GSE63312PRJNA267255

REPOSITORIES: GEO, ArrayExpress, ENA

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Publications


Mutant RAS oncoproteins activate signaling molecules that drive oncogenesis in multiple human tumors including acute myelogenous leukemia (AML). However, the specific functions of these pathways in AML are unclear, thwarting the rational application of targeted therapeutics. To elucidate the downstream functions of activated NRAS in AML, we used a murine model that harbors Mll-AF9 and a tetracycline-repressible, activated NRAS (NRAS(G12V)). Using computational approaches to explore our gene-expr  ...[more]

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