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)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Mufson, R Allan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
Dail, Monique; Wong, Jason; Lawrence, Jessica et al. (2014) Loss of oncogenic Notch1 with resistance to a PI3K inhibitor in T-cell leukaemia. Nature 513:512-6
Jain, Nitin; Curran, Emily; Iyengar, Neil M et al. (2014) Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial. Clin Cancer Res 20:490-8
North, Matthew; Shuga, Joe; Fromowitz, Michele et al. (2014) Modulation of Ras signaling alters the toxicity of hydroquinone, a benzene metabolite and component of cigarette smoke. BMC Cancer 14:6
Stieglitz, Elliot; Liu, Y Lucy; Emanuel, Peter D et al. (2014) Mutations in GATA2 are rare in juvenile myelomonocytic leukemia. Blood 123:1426-7
Lu, Jing; Zavorotinskaya, Tatiana; Dai, Yumin et al. (2013) Pim2 is required for maintaining multiple myeloma cell growth through modulating TSC2 phosphorylation. Blood 122:1610-20
Xu, Jin; Haigis, Kevin M; Firestone, Ari J et al. (2013) Dominant role of oncogene dosage and absence of tumor suppressor activity in Nras-driven hematopoietic transformation. Cancer Discov 3:993-1001
Chang, Tiffany; Krisman, Kimberly; Theobald, Emily Harding et al. (2013) Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice. J Clin Invest 123:335-9
Li, Qing; Bohin, Natacha; Wen, Tiffany et al. (2013) Oncogenic Nras has bimodal effects on stem cells that sustainably increase competitiveness. Nature 504:143-7
Diaz-Flores, Ernesto; Goldschmidt, Hana; Depeille, Philippe et al. (2013) PLC-ýý and PI3K link cytokines to ERK activation in hematopoietic cells with normal and oncogenic Kras. Sci Signal 6:ra105
Shieh, Angell; Ward, Ashley F; Donlan, Kegan L et al. (2013) Defective K-Ras oncoproteins overcome impaired effector activation to initiate leukemia in vivo. Blood 121:4884-93

Showing the most recent 10 out of 27 publications