The dimerization domains of MLL are potential therapeutic targets in t(4;11)-leukemias

Abstract

The human MLL protein – as well as the leukemogenic AF4-MLL fusion protein are specifically hydrolyzed by the endopeptidase Taspase1. The resulting protein fragments are able to form an intramolcular dimer which is necessary for complex formation and stability of both proteins. We have dissected the two dimerization domains, named FYRN and FYRC, by B-2-H experiments, pull-down experiments using recombinant proteins and Co-IP studies in mammalian cells. The minimal interaction domains was experimentally defined as 50 amino acid long peptides that are still able to confer specific binding in vitro and in vivo. Overexpression of these protein fragments affects the MLL wildtype and AF4-MLL fusion protein by competing with the intramolecular dimerization process. This leads to increased levels of apoptosis, prevention of complex fomation and the specific degradation of the leukemogenic AF4-MLL fusion protein. These findings will be quite helpful to design rational therapies for t(4;11) leukemia.