Development of an LEDGF/p75 based strategy for the treatment of MLL-rearranged leukemia.

MLL-rearranged (MLL-r) acute leukemias represent a genetically distinct subset of leukemia originating from rearrangements in the MLL (Mixed lineage leukemia) gene. MLL-r leukemia is especially prevalent in infants (0-1y) and compared to most types of leukemia, patients face an adverse clinical outcome (15-40 % event-free survival at 48 months). New treatment strategies are urgently needed since no specific treatment for these patients is available. In our previous project we validated the interaction of MLL with LEDGF/p75 (Lens Epithelium Derived Growth Factor/p75) as a new therapeutic target and initiated drug discovery targeting this interaction. MLL is targeted to the chromatin through its interaction with LEDGF/p75 which drives HoxA gene expression. Deregulation of HoxA genes is one of the hallmarks of MLL-r leukemia. Strategies disrupting this interaction have been shown to revert cellular transformation. In this project, we will develop lead compounds targeting the MLL-LEDGF/p75 interaction. In addition, we will study the role of HRP2 in MLL-r leukemia. HRP2 is the only human protein with a similar domain structure as LEDGF/p75. Preliminary results indicate that HRP2 is part of the MLL complex and affects colony formation of MLL-rearranged cell lines, indicating that HRP2 might play a similar role as LEDGF/p75 in MLL-r leukemia. In the light of our drug development efforts, it is crucial to understand the role of HRP2.