FUNCTIONAL ANALYSIS OF SALL4

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 急性髓性白血病（AML）的发病机制涉及一系列通过原癌基因激活或肿瘤抑制基因失活的进行性遗传改变。马博士发现了一种新的癌基因SALL 4，它在人类白血病细胞系和几乎100%的原发性急性髓系白血病细胞中组成型表达。过表达SALL 4 B的转基因小鼠表现出骨髓增生异常（MDS）样特征，随后出现急性髓性白血病（AML）转化。此外，PI已经显示SALL 4A和SALL 4 B能够结合到Wnt信号通路的必需组分-连环蛋白。该项目的基本假设是SALL 4的异常组成型表达在AML中是致癌的。为了检验这一假设，该项目的具体目标如下： 具体目标I：确定SALL 4亚型在AML发生和/或进展中的分子机制。 具体目标II：确定SALL 4亚型如何影响启动或导致AML进展的信号通路。 这些研究将提供关于SALL 4亚型在AML中所起作用的详细信息。所获得的知识将提供造血细胞分化和白血病发生的更好的理解，并可能导致新的AML治疗靶点的识别。

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. Dr. Ma has discovered a new oncogene, SALL4, which is constitutively expressed in human leukemia cell lines and almost 100% of primary acute myeloid leukemia cells. Transgenic mice overexpressing SALL4B exhibited myelodysplastic (MDS)-like feactures and subsequently, acute myeloid leukemia (AML) transformation. In addition, PI has shown that SALL4A and SALL4B are able to bind to ¿-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, the specific aims of this project are as follows: Specific Aim I: Determine molecular mechanism(s) of SALL4 isoforms in the initiation and/or the progression of AML. Specific Aim II: 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.