TARGET FACULTY RESEARCH/FUNCTIONAL ANALYSIS OF SALL4

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。急性髓系白血病(AML)的发病机制涉及一系列通过原癌基因激活或抑癌基因失活而导致的进行性基因改变。PI项目发现了一个新的癌基因SALL4，它在人类白血病细胞系和几乎100%的原发急性髓系白血病细胞中有结构性表达。过量表达SALL4B的转基因小鼠表现出骨髓增生异常(MDS)样特征，随后出现急性髓系白血病(AML)转化。此外，PI还表明SALL4A和SALL4B能够与Wnt信号通路的重要组成部分--β-连环蛋白结合。这个项目背后的假设是，SALL4的异常结构性表达在AML中是致癌的。为了验证这一假说，我们提出了两个具体的目标：1)确定SALL4亚型在急性髓细胞白血病发病和/或进展中的分子机制(S)；2)确定SALL4亚型如何影响启动或导致AML进展的信号通路。这些研究将提供有关SALL4亚型在AML中所起作用的详细信息。所获得的知识将提供对造血细胞分化和白血病发生的更好的理解，并可能导致识别AML的新的治疗靶点。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The pathogenesis of acute myeloid leukemia (AML) involves a progressive set of genetic alterations via activation of proto-oncogenes or inactivation of tumor suppressors. The project PI has discovered a new oncogene, SALL4, which is constitutively expressed in human leukemia cell lines and almost 100% primary acute myeloid leukemia cells. Transgenic mice overexpressing SALL4B exhibited myelodysplastic (MDS)-like features and subsequently, acute myeloid leukemia (AML) transformation. In addition, PI has shown that SALL4A and SALL4B are able to bind to beta-catenin, an essential component for Wnt signal pathway. The hypothesis underlying this project is that aberrant constitutive expression of SALL4 is oncogenic in AML. To test this hypothesis, we propose two the specific aims: 1) determine molecular mechanism(s) of SALL4 isoforms in the initiation and/or the progression of AML, and 2) determine how SALL4 isoforms affect signaling pathways, which initiate or cause progression of AML. These studies will provide detailed information on the role played by SALL4 isoforms in AML. The knowledge obtained will provide a better understanding of hematopoietic cell differentiation and leukemogenesis, and may lead to the identification of novel therapeutic targets for AML.