The overall goal of this proposal is to understand the mechanism of blood cell transformation during leukemogenesis. Chromosomal translocations are frequently involved in the process of leukemia development. Among various translocations, t(8;21)(q22;q22) is reported in 8-20% cases of acute myeloid leukemia (AML) depending on the genetic background and geographic locations of the population, which makes it one of the most common translocations associated with AML. This translocation leads to the fusion of the AML1 and ETO genes and generates various forms of AML1-ETO fusion proteins. In the previous funding period, we discovered that additional mutations, such as abnormal hematopoietic growth factor signal transduction due to loss of one of the human sex chromosomes or deletion or mutation of the NHR4 zinc finger domain of AML1- ETO, cooperate with t(8;21) in AML development. Furthermore, we identified a DNA and RNA binding domain containing protein called SON that specifically interacts with the NHR4 zinc finger domain of ETO. In the current funding period, we propose to test the hypotheses that disrupting IL-3 and/or GM-CSF signal transduction is a major additional mutation associated with loss of one human sex chromosome in t(8;21) leukemia development and that SON is a critical factor in hematopoietic cells. The studies proposed in Specific Aim 1 will define the role of IL3 and GM-CSF receptor signal transduction in the development of t(8;21) related leukemia. The studies proposed in Specific Aim 2 will characterize the role of SON in AML1-ETO involved leukemogenesis. The studies proposed in Specific Aim 3 will analyze the biological function of SON in hematopoiesis. These studies will address important questions about hematopoiesis and leukemogenesis, which may provide valuable insight into the treatment of leukemia and other cancers.

Public Health Relevance

t(8;21) is a common chromosomal translocation in AML. We propose to study how abnormal signaling of growth factors IL3 and GM-CSF and a protein SON are involved in t(8;21) associated leukemogenesis and how SON is involved in hematopoiesis. These studies will 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 #
5R01CA096735-10
Application #
8196740
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Mufson, R Allan
Project Start
2002-07-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
10
Fiscal Year
2012
Total Cost
$358,571
Indirect Cost
$126,486
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; Yan, Ming; Ahn, Eun-Young et al. (2013) Attenuation of AML1-ETO cellular dysregulation correlates with increased leukemogenic potential. Blood 121:3714-7
Ahn, Erin Eun-Young; Higashi, Tsunehito; Yan, Ming et al. (2013) SON protein regulates GATA-2 through transcriptional control of the microRNA 23a~27a~24-2 cluster. J Biol Chem 288:5381-8
Matsuura, Shinobu; Yan, Ming; Lo, Miao-Chia et al. (2012) Negative effects of GM-CSF signaling in a murine model of t(8;21)-induced leukemia. Blood 119:3155-63
Lam, Kentson; Zhang, Dong-Er (2012) RUNX1 and RUNX1-ETO: roles in hematopoiesis and leukemogenesis. Front Biosci (Landmark Ed) 17:1120-39
Boyapati, Anita; Ren, Bing; Zhang, Dong-Er (2011) SERPINB13 is a novel RUNX1 target gene. Biochem Biophys Res Commun 411:115-20
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
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
Dayyani, Farshid; Wang, Jianfeng; Yeh, Jing-Ruey J et al. (2008) Loss of TLE1 and TLE4 from the del(9q) commonly deleted region in AML cooperates with AML1-ETO to affect myeloid cell proliferation and survival. Blood 111:4338-47
Hines, Robert; Boyapati, Anita; Zhang, Dong-Er (2007) Cell type dependent regulation of multidrug resistance-1 gene expression by AML1-ETO. Blood Cells Mol Dis 39:297-306
Peterson, Luke F; Lo, Miao-Chia; Okumura, Akiko Joo et al. (2007) Inability of RUNX1/AML1 to breach AML1-ETO block of embryonic stem cell definitive hematopoiesis. Blood Cells Mol Dis 39:321-8

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