Functional inactivation of the AF4-MLL oncoprotein

Introduction: We have demonstrated that transduction and recombinant expression of the AF4-MLL oncoprotein in hematopoietic stem/precursor cells is sufficient to induce the development of proB ALL in a mouse model system (Bursen et al., 2010). Results: Here, we present our data on our efforts to functionally inactivate the AF4-MLL fusion protein. First, we targeted the FYRN/FYRC heterodimerization domain, demonstrating that interference with the heterodimerization process leads to proteasomal degradation of AF4-MLL. Next, we investigated Taspase1 which processes the AF4-MLL fusion protein prior to heterodimerization. We unraveled the mechanism which is required for the sequential activation of Taspase1. This knowledge can now be translated into the design of rational drugs that could potentially be used in the future for the treatment of t(4;11) leukemia patients.

This work is supported by a grant from the Deutsche Krebshilfe (108400) to RM.