The pathogenesis of acute myeloid leukemia (AML) involves a progressive set of genetic alterations via activation of proto-oncogenes or inactivation of tumor suppressors. Our lab 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, we have shown that SALL4A and SALL4B are able to bind to ß-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, 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.