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NRASG12V oncogene mediates self-renewal in acute myelogenous leukemia

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

ORGANISM(S): Mus musculus

SUBMITTER: Zohar Sachs

PROVIDER: E-GEOD-49089 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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NRASG12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia.

Sachs Zohar Z LaRue Rebecca S RS Nguyen Hanh T HT Sachs Karen K Noble Klara E KE Mohd Hassan Nurul Azyan NA Diaz-Flores Ernesto E Rathe Susan K SK Sarver Aaron L AL Bendall Sean C SC Ha Ngoc A NA Diers Miechaleen D MD Nolan Garry P GP Shannon Kevin M KM Largaespada David A DA

Blood 20141014 22

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]

PMID: 25316678

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NRASG12V mediates leukemia self renewal [Microarray]

Project description: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. Mice harboring NRASG12V/Mll-AF9 AML were treated with doxycyline to abolish NRASG12V expression. Leukemia samples were harvested at 12 hour intervals after doxycyline treatment. RNA was extracted from these samples and submitted for gene expression microarray analysis

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NRASG12V mediates leukemia self renewal [RNA-Seq]

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Project description: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 NRASG12V-Mll-AF9 AML cells were treated in vitro for 24 hours with Ras-pathway inhibitors. RNA was extracted from these cells and submitted for RNA sequencing.

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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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