AML1-ETO is a DNA binding fusion protein generated from t(8;21). This chromosomal translocation is one of the most common genetic abnormalities in acute myeloid leukemia (AML), identified in over 10% of all cases. Studies from our own work and from others have demonstrated that AML1-ETO plays an important role in the development of leukemia. However, it is not sufficient by itself for leukemia development. Interestingly, multiple forms of AML1-ETO are present in t(8;21) leukemia samples due to alternative RNA splicing and deletion mutations. However, most of the current studies are focused on the function of the full length AML1-ETO in leukemogenesis. The role played by these other shorter forms have been largely ignored. Recently, we performed bone marrow transplantations on mice transduced with a full length AML1-ETO expression vector. Three of these mice developed AML, two of which contained C-terminal truncations as the only form of AML1-ETO present in the tumor. Further mouse model analysis revealed that the C-terminal truncated AML1-ETO was a potent inducer of leukemia. These findings lead to the hypothesis that in addition to the already described interactions between AML1-ETO and the histone deacetylase complexes, alterations of protein - protein interactions in the presence of the shorter forms of AML1-ETO or additional genetic mutations which disrupt protein interactions with the C-terminal portion of full length AML1-ETO may contribute to t (8;21) involved leukemogenesis. We have developed three specific aims to test this hypothesis.
Specific Aim #1 will analyze the effect of various forms of AML1-ETO on leukemogenesis and hematopoiesis using mouse models.
Specific Aim #2 will study the effect of various forms of AML1-ETO on cell survival, proliferation, and differentiation using a well-established multipotent hematopoietic cell line.
Specific Aim #3 will characterize proteins interacting with AML-ETO to understand the molecular mechanism of AML1-ETO involved leukemia development. We have established animal and cell line models and biochemical approaches to pursue these proposed studies. The experiments may provide valuable insight into the molecular mechanisms of leukemogenesis and therapeutic drug designs in cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA104509-05S1
Application #
7917973
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mufson, R Allan
Project Start
2004-07-16
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2010-04-30
Support Year
5
Fiscal Year
2009
Total Cost
$41,715
Indirect Cost
Name
University of California San Diego
Department
Pathology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Gao, X N; Yan, F; Lin, J et al. (2015) AML1/ETO cooperates with HIF1? to promote leukemogenesis through DNMT3a transactivation. Leukemia 29:1730-40
DeKelver, Russell C; Lewin, Benjamin; Weng, Stephanie et al. (2014) RUNX1-ETO induces a type I interferon response which negatively effects t(8;21)-induced increased self-renewal and leukemia development. Leuk Lymphoma 55:884-91
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DeKelver, Russell C; Yan, Ming; Ahn, Eun-Young et al. (2013) Attenuation of AML1-ETO cellular dysregulation correlates with increased leukemogenic potential. Blood 121:3714-7
DeKelver, Russell C; Lewin, Benjamin; Lam, Kentson et al. (2013) Cooperation between RUNX1-ETO9a and novel transcriptional partner KLF6 in upregulation of Alox5 in acute myeloid leukemia. PLoS Genet 9:e1003765
Lo, Miao-Chia; Peterson, Luke F; Yan, Ming et al. (2012) Combined gene expression and DNA occupancy profiling identifies potential therapeutic targets of t(8;21) AML. Blood 120:1473-84
Shia, Wei-Jong; Okumura, Akiko J; Yan, Ming et al. (2012) PRMT1 interacts with AML1-ETO to promote its transcriptional activation and progenitor cell proliferative potential. Blood 119:4953-62
Arnold, Christopher P; Tan, Ruoying; Zhou, Baiyu et al. (2011) MicroRNA programs in normal and aberrant stem and progenitor cells. Genome Res 21:798-810

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