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 #
5R01CA104509-09
Application #
8444329
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Mufson, R Allan
Project Start
2003-12-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
9
Fiscal Year
2013
Total Cost
$284,008
Indirect Cost
$100,184
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
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
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
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
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
Yan, Ming; Ahn, Eun-Young; Hiebert, Scott W et al. (2009) RUNX1/AML1 DNA-binding domain and ETO/MTG8 NHR2-dimerization domain are critical to AML1-ETO9a leukemogenesis. Blood 113:883-6
Okumura, Akiko J; Peterson, Luke F; Okumura, Fumihiko et al. (2008) t(8;21)(q22;q22) Fusion proteins preferentially bind to duplicated AML1/RUNX1 DNA-binding sequences to differentially regulate gene expression. Blood 112:1392-401
Li, Zejuan; Lu, Jun; Sun, Miao et al. (2008) Distinct microRNA expression profiles in acute myeloid leukemia with common translocations. Proc Natl Acad Sci U S A 105:15535-40
Gardini, Alessandro; Cesaroni, Matteo; Luzi, Lucilla et al. (2008) AML1/ETO oncoprotein is directed to AML1 binding regions and co-localizes with AML1 and HEB on its targets. PLoS Genet 4:e1000275
Ahn, Eun-Young; Yan, Ming; Malakhova, Oxana A et al. (2008) Disruption of the NHR4 domain structure in AML1-ETO abrogates SON binding and promotes leukemogenesis. Proc Natl Acad Sci U S A 105:17103-8
Boyapati, Anita; Yan, Ming; Peterson, Luke F et al. (2007) A leukemia fusion protein attenuates the spindle checkpoint and promotes aneuploidy. Blood 109:3963-71

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