This competitive revision application proposes to substantially extend the scope of our funded research by exploiting novel unpublished observations that we have made in mice in which we have activated expression of a latent oncogenic LSL-NrasG12D """"""""knock in"""""""" allele in hematopoietic cells. In studies supported by this award, we used the interferon-regulated Mx1-Cre transgene to ablate Nf1 or to induce KrasG12D expression from the endogenous locus. This resulted in an aggressive myeloproliferative disease (MPD) in Mx1-Cre, KrasG12D mice that is uniformly fatal by 4 months of age (1, 2). Mx1-Cre, Nf1flox/flox mice also develop MPD, but this disease is less aggressive. Although MPD frequently progresses to acute myeloid leukemia (AML) in human patients (3), neither Nf1 nor Kras mutant mice spontaneously develop acute leukemia. We therefore performed RIM with the MOL4070LTR virus (4, 5) in an effort to induce cooperating mutations. This approach has been successful in Nf1 mutant mice with ~25% of the animals progressing to AML. However, Kras mutant mice predominately develop T lineage acute lymphoblastic leukemia (T-ALL) and AML is uncommon (data not shown). While we are pursuing these unexpected findings, we were disappointed that we were unable to model the common occurrence of a somatic RAS gene mutation found in human AML. Two novel observations in Mx1-Cre, NrasG12D mice form the basis of this proposed competitive revision. First, we unexpectedly observe markedly different hematologic phenotypes in Mx1-Cre, KrasG12D and Mx1-Cre, NrasG12D mice that are not injected with MOL4070LTR. Second, RIM efficiently induced AML in Mx1-Cre, NrasG12D mice that closely models the human disease. Based on these data, we propose the following additional aims that we will complete over the next two years: 1) To perform genetic and functional studies to identify domains within the K-RasG12D and NRasG12D proteins that underlie their different effects in hematopoietic cells. 2) To investigator mechanisms of response and resistance to molecularly targeted agents in AMLs characterized by NrasG12D expression. This application requests supplemental funds to support a new research technician who will work closely with Dr. Xu to underwrite costs of animal care, reagents, and DNA sequencing, and to purchase a key piece of equipment.
This proposal will use a new strain of mice that carries a mutation in a gene that is frequently mutated in human leukemia and other cancers. We have used these mice to develop an accurate model of acute myeloid leukemia (AML) and will use them to test new strategies for treating this aggressive cancer and for uncovering mechanisms of resistance that lead to relapse. The long-term goal of this research is to develop and implement better treatments for AML, which is an important cause of cancer morbidity and death.
| 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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