Molecular and pharmacological inhibition of the t(4;11) fusion proteins MLL-AF4 and AF4-MLL

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The chromosomal translocation t(4;11) is associated with a high-risk acute leukemia (proB ALL) in infants, children and adults, however, with a poor prognosis (survival is ~40%). The expressed fusion proteins MLL-AF4 and AF4-MLL have already been classified as onocproteins. The results of our scientific research during the last years on the pathology of these fusion proteins have brought us to a point where we can foresee how this type of leukemia can be treated at the molecular level or by using pharmacological treatment strategies. Here, we want to test our knowledge in pre¬clinical models, which can then further be used for clinical studies. The prerequisite for this project is our knowledge to selectively disable oncogenic functions deriving from both fusion proteins (MLL-AF4 and AF4-MLL). The planned experiments will be carried out in appropriate cell culture models, as well as in patient-cell derived PDX mouse models for the validation of our concepts. Our concept clearly separates from strategies of others, namely to inhibit specifically the Menin1/MLL interactions, BET-proteins or DOT1L, because those strategies inhibit essential functions of MLL and AF4 in normal cells - which is avoided in our experimental strategy.