The p21[ras] (Ras) family of signal switch proteins is deregulated in myeloid malignancies by genetic mechanisms that include NRAS and KF^S2 point mutations, the BCR-ABL fusion, PTPN11 mutations, and NF1 inactivation. We developed accurate mouse models of myeloproliferative disease (MPD) by exploiting the Mx1-Cre transgene to ablate a conditional mutant Nf1 allele or to activate oncogenic Kras[G121D] expression from its endogenous promoter (1, 2). In recent work, we exploited this strategy to induce endogenous oncogenic Nras[G12D] expression in hematopoietic cells, and unexpectedly observed marked phenotypic differences in Kras and Nras mutant mice. Studies in this new model formed the basis of a successful application for supplemental funding support through the ARRA to extend the scope of this R37 award to investigate leukemogenesis in Nras mice. We have made extensive use of retroviral insertional mutagenesis to induce progression from MPD to acute myeloid leukemia (AML) and T lineage acute lymphoblastic leukemia (T-ALL) in Nf1, Kras, and Nras mutant mice, and we are harnessing these aggressive and genetically heterogeneous cancers to investigate mechanisms of drug response and resistance in vivo.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Method to Extend Research in Time (MERIT) Award (R37)
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No Study Section (in-house review) (NSS)
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Mufson, R Allan
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University of California San Francisco
Schools of Medicine
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Wandler, Anica; Shannon, Kevin (2018) Mechanistic and Preclinical Insights from Mouse Models of Hematologic Cancer Characterized by Hyperactive Ras. Cold Spring Harb Perspect Med 8:
Bielski, Craig M; Donoghue, Mark T A; Gadiya, Mayur et al. (2018) Widespread Selection for Oncogenic Mutant Allele Imbalance in Cancer. Cancer Cell 34:852-862.e4
Burgess, Michael R; Hwang, Eugene; Mroue, Rana et al. (2017) KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer. Cell 168:817-829.e15
Maertens, Ophélia; McCurrach, Mila E; Braun, Benjamin S et al. (2017) A Collaborative Model for Accelerating the Discovery and Translation of Cancer Therapies. Cancer Res 77:5706-5711
Fenouille, Nina; Bassil, Christopher F; Ben-Sahra, Issam et al. (2017) The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia. Nat Med 23:301-313
White, Yasmine; Bagchi, Aditi; Van Ziffle, Jessica et al. (2016) KRAS insertion mutations are oncogenic and exhibit distinct functional properties. Nat Commun 7:10647
Shankar, Sunita; Pitchiaya, Sethuramasundaram; Malik, Rohit et al. (2016) KRAS Engages AGO2 to Enhance Cellular Transformation. Cell Rep 14:1448-1461
Wong, Jasmine C; Weinfurtner, Kelley M; Alzamora, Maria Del Pilar et al. (2015) Functional evidence implicating chromosome 7q22 haploinsufficiency in myelodysplastic syndrome pathogenesis. Elife 4:
Zhao, Zhen; Chen, Chi-Chao; Rillahan, Cory D et al. (2015) Cooperative loss of RAS feedback regulation drives myeloid leukemogenesis. Nat Genet 47:539-43
Burgess, Michael R; Hwang, Eugene; Firestone, Ari J et al. (2014) Preclinical efficacy of MEK inhibition in Nras-mutant AML. Blood 124:3947-55

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