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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA072614-17
Application #
8434826
Study Section
Special Emphasis Panel (NSS)
Program Officer
Mufson, R Allan
Project Start
1997-02-15
Project End
2017-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
17
Fiscal Year
2013
Total Cost
$286,486
Indirect Cost
$101,058
Name
University of California San Francisco
Department
Pediatrics
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
White, Yasmine; Bagchi, Aditi; Van Ziffle, Jessica et al. (2016) KRAS insertion mutations are oncogenic and exhibit distinct functional properties. Nat Commun 7:10647
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
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:
Shannon, Kevin M (2014) CCR4 drives ATLL jail break. J Exp Med 211:2485
Stieglitz, Elliot; Liu, Y Lucy; Emanuel, Peter D et al. (2014) Mutations in GATA2 are rare in juvenile myelomonocytic leukemia. Blood 123:1426-7
Burgess, Michael R; Hwang, Eugene; Firestone, Ari J et al. (2014) Preclinical efficacy of MEK inhibition in Nras-mutant AML. Blood 124:3947-55
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
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
Sachs, Zohar; LaRue, Rebecca S; Nguyen, Hanh T et al. (2014) NRASG12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia. Blood 124:3274-83
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

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