Project A4: Dissection of the function of the "Lymphoid enhancer-binding factor 1" (Lef1) in acute myeloid leukemia
During the last funding periods it was shown that aberrant expression of Lef1 causes AML in mice. Furthermore, the project demonstrated that the expression level of LEF1 is a novel prognostic factor in normal karyotype AML, predicting relapse-free, event-free, and overall survival. Knockdown of endogenous Lef1 and overexpression of different Lef1 mutants documented an essential role of wildtype Lef1 for normal HSC function and underlined that the N-terminally deleted Lef1, missing the β-catenin binding site, is an active protein with distinct DNA-binding properties and hematopoietic activity up to the level of short-term repopulat-ing stem cells. However, several aspects of LEF1-induced leukemogenesis are still not well understood. Importantly, Lef1-induced leukemias develop after longer latency time in mice and LEF1 expression in human AML occurs in the context of a variety of molecular alterations. So far, it is not understood how LEF1 contrib-utes to the initiation and maintenance of AML in the context of other AML alterations. There are no data whether AML oncogenes target and upregulate LEF1 directly or indirectly via regulatory networks. Furthermore, it is unknown to which extent the N-terminally deleted, naturally occurring LEF1 isoform, which has lost β-catenin binding properties, contributes to leukemogenesis. The proposal aims at these open questions. The work pro-gram will focus on AML1-ETO-positive AML and CDX2-positive AML, based on data that are pointing to a key role of LEF1 in the biology of these AML.
For a current list of project-related publications, please go to this page