NRASG12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia. Sachs, Z., LaRue, R. S., Nguyen, H. T., Sachs, K., Noble, K. E., Hassan, N. A. M., Diaz-Flores, E., Rathe, S. K., Sarver, A. L., Bendall, S. C., Ha, N. A., Diers, M. D., Nolan, G. P., Shannon, K. M., & Largaespada, D. A. Blood, January, 2014. ![NRASG12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex 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 employed a murine model that harbors Mll-AF9 and a tetracycline repressible, activated NRAS (NRASG12V). By employing computational approaches to explore our gene expression datasets, we found that NRASG12V enforced the leukemia self-renewal gene expression signature and was required to maintain an MLL-AF9 and MYB-dependent leukemia self-renewal gene expression program. NRASG12V was required for leukemia self-renewal independently of its effects on growth and survival. Analysis of the gene expression patterns of leukemic subpopulations revealed the NRASG12V-mediated leukemia self-renewal signature is preferentially expressed in the leukemia stem cell-enriched subpopulation. In a multiplexed analysis of RAS-dependent signaling, Mac-1Low cells, which harbor leukemia stem cells, were preferentially sensitive to NRASG12V withdrawal. NRASG12V maintained leukemia self-renewal through mTOR and MEK pathway activation, implicating these pathways as potential targets for cancer stem cell-specific therapies. Together, these experimental results define a RAS oncogene-driven function that is critical for leukemia maintenance and represents a novel mechanism of oncogene addiction.
@article{sachs_nrasg12v_2014,
title = {{NRASG}12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia},
copyright = {Copyright {\textcopyright} 2014 American Society of Hematology},
issn = {0006-4971, 1528-0020},
url = {http://www.bloodjournal.org/content/early/2014/10/14/blood-2013-08-521708},
doi = {10.1182/blood-2013-08-521708},
abstract = {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 employed a murine model that harbors Mll-AF9 and a tetracycline repressible, activated NRAS (NRASG12V). By employing computational approaches to explore our gene expression datasets, we found that NRASG12V enforced the leukemia self-renewal gene expression signature and was required to maintain an MLL-AF9 and MYB-dependent leukemia self-renewal gene expression program. NRASG12V was required for leukemia self-renewal independently of its effects on growth and survival. Analysis of the gene expression patterns of leukemic subpopulations revealed the NRASG12V-mediated leukemia self-renewal signature is preferentially expressed in the leukemia stem cell-enriched subpopulation. In a multiplexed analysis of RAS-dependent signaling, Mac-1Low cells, which harbor leukemia stem cells, were preferentially sensitive to NRASG12V withdrawal. NRASG12V maintained leukemia self-renewal through mTOR and MEK pathway activation, implicating these pathways as potential targets for cancer stem cell-specific therapies. Together, these experimental results define a RAS oncogene-driven function that is critical for leukemia maintenance and represents a novel mechanism of oncogene addiction.},
language = {en},
urldate = {2014-10-22},
journal = {Blood},
author = {Sachs, Zohar and LaRue, Rebecca S. and Nguyen, Hanh T. and Sachs, Karen and Noble, Klara E. and Hassan, Nurul Azyan Mohd and Diaz-Flores, Ernesto and Rathe, Susan K. and Sarver, Aaron L. and Bendall, Sean C. and Ha, Ngoc A. and Diers, Miechaleen D. and Nolan, Garry P. and Shannon, Kevin M. and Largaespada, David A.},
month = jan,
year = {2014},
pmid = {25316678},
pages = {blood--2013--08--521708}
}
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A."],"year":2014,"bibtype":"article","biburl":"https://www.dropbox.com/s/6cn84hmkr6b4v53/cytof-uk.bib?dl=1","bibdata":{"bibtype":"article","type":"article","title":"NRASG12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia","copyright":"Copyright © 2014 American Society of Hematology","issn":"0006-4971, 1528-0020","url":"http://www.bloodjournal.org/content/early/2014/10/14/blood-2013-08-521708","doi":"10.1182/blood-2013-08-521708","abstract":"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 employed a murine model that harbors Mll-AF9 and a tetracycline repressible, activated NRAS (NRASG12V). By employing computational approaches to explore our gene expression datasets, we found that NRASG12V enforced the leukemia self-renewal gene expression signature and was required to maintain an MLL-AF9 and MYB-dependent leukemia self-renewal gene expression program. NRASG12V was required for leukemia self-renewal independently of its effects on growth and survival. Analysis of the gene expression patterns of leukemic subpopulations revealed the NRASG12V-mediated leukemia self-renewal signature is preferentially expressed in the leukemia stem cell-enriched subpopulation. In a multiplexed analysis of RAS-dependent signaling, Mac-1Low cells, which harbor leukemia stem cells, were preferentially sensitive to NRASG12V withdrawal. NRASG12V maintained leukemia self-renewal through mTOR and MEK pathway activation, implicating these pathways as potential targets for cancer stem cell-specific therapies. 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