AML1-ETO is a DNA binding fusion protein generated from t(8;21)(q22;q22). This chromosomal translocation is one of the most common genetic abnormalities in acute myeloid leukemia (AML), identified in over 10% of all cases. Our own studies and those of others using both human and mouse models 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. Most of our current understanding of t(8;21) in leukemogenesis comes from studies of the full length AML1-ETO. The role played by these other shorter forms is largely unknown. During the previous funding period, we demonstrated the existence of an alternatively spliced isoform of t(8;21), AML1-ETO9a, which includes one extra exon 9a and generates a fusion protein that lacks 178 amino acids comprising the C-terminus of the full length AML1-ETO. More importantly, AML1-ETO9a is highly leukemogenic in a mouse model of retrovirus vector mediated transduction- hematopoietic cell transplantation. These findings lead to the hypothesis that the most critical domains of AML1-ETO for leukemogenesis are located within the N-terminal portion of this fusion protein covered by AML1-ETO9a, which function via regulation of specific target gene expression and interaction with key complexes involved in basic cellular events. We have developed three specific aims to test this hypothesis.
Specific Aim #1 will analyze the effect of AML1-ETO9a on leukemogenesis and hematopoiesis using human hematopoietic cells and using AML1-ETO9a knock-in mice.
Specific Aim #2 will study the effect of AML1- ETO9a on leukemogenesis by identifying and characterizing its direct target genes. We have performed combined gene expression-promoter occupancy profiling arrays with primary AML1-ETO9a induced leukemic cells to identify molecular targets modulated by this leukemogenic fusion protein.
Specific Aim #3 will characterize proteins interacting with AML1-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. 1

Public Health Relevance

t(8;21) is a common chromosomal translocation in acute myeloid leukemia. We propose to establish useful t(8;21) mouse models for clinical drug testing and to analyze the molecular mechanism of t(8;21) in leukemogenesis. These studies will provide useful tools and address important questions about hematopoiesis and leukemogenesis, which may provide valuable insight into the treatment of leukemia and other cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA104509-10
Application #
8616343
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Mufson, R Allan
Project Start
2003-12-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
10
Fiscal Year
2014
Total Cost
$271,922
Indirect Cost
$95,921
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
Gao, X N; Yan, F; Lin, J et al. (2015) AML1/ETO cooperates with HIF1α 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
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, M-C; Peterson, L F; Yan, M et al. (2013) JAK inhibitors suppress t(8;21) fusion protein-induced leukemia. Leukemia 27:2272-9
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
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
Ahn, Eun-Young; DeKelver, Russell C; Lo, Miao-Chia et al. (2011) SON controls cell-cycle progression by coordinated regulation of RNA splicing. Mol Cell 42:185-98
Speck, Nancy A; Vakoc, Christopher R (2010) PAF is in the cabal of MLL1-interacting proteins that promote leukemia. Cancer Cell 17:531-2

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