t(8;21) and SON in Blood Cell Proliferation and Differentiation

描述(申请人提供)：这项建议的总体目标是了解白血病发生过程中血细胞转化的机制。染色体易位经常参与白血病的发生发展过程。在各种易位中，t(8；21)(q22；q22)在8-20%的急性髓系白血病(AML)病例中被报道，这取决于遗传背景和人群的地理位置，这使其成为与AML相关的最常见的易位之一。这种易位导致AML1和ETO基因的融合，并产生各种形式的AML1-ETO融合蛋白。在之前的资助期间，我们发现了额外的突变，如人类性染色体丢失引起的造血生长因子信号转导异常，或者AML1-ETO的NHR4锌指结构域的缺失或突变，在AML的发生中与t(8；21)协同作用。此外，我们还鉴定了一个含有DNA和RNA结合域的蛋白质SON，它与ETO的NHR4锌指结构域特异地相互作用。在目前的资助期，我们建议测试以下假设：干扰IL-3和/或GM-CSF信号转导是与t(8；21)白血病发生中的一条人类性染色体丢失相关的主要额外突变，并且该SON是造血细胞中的关键因素。在特定目的1中提出的研究将确定IL3和GM-CSF受体信号转导在t(8；21)相关性白血病发生中的作用。在特定目标2中提出的研究将表征SON在AML1-ETO参与白血病发生中的作用。在特定目标3中提出的研究将分析SON在造血中的生物学功能。这些研究将解决有关造血和白血病发生的重要问题，这可能为白血病和其他癌症的治疗提供有价值的见解。公共卫生相关性：T(8；21)是AML中常见的染色体易位。我们建议研究生长因子IL3、GM-CSF和一个蛋白SON的异常信号如何参与t(8；21)相关白血病的发生，以及SON如何参与造血。这些研究将解决有关造血和白血病发生的重要问题，这可能为白血病和其他癌症的治疗提供有价值的见解。

DESCRIPTION (provided by applicant): 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.