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.
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.
|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; Komeno, Yukiko; Stevenson, Kristen E et al. (2012) Expression of the runt homology domain of RUNX1 disrupts homeostasis of hematopoietic stem cells and induces progression to myelodysplastic syndrome. Blood 120:4028-37|
|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|
|Lam, Kentson; Zhang, Dong-Er (2012) RUNX1 and RUNX1-ETO: roles in hematopoiesis and leukemogenesis. Front Biosci (Landmark Ed) 17:1120-39|
|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|
|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|
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