LEDGF/p75 chromatin tethering as a target to treat Jpo2 and MLL dependent malignancies

When all links between genes associated with disease development (diseaseome) and virushost interactions (infectome) are mapped, a network emerges revealing common genetic origin of many diseases and viral infections. In addition, interaction nodes or protein hubs appear with a central function in many disorders or infections. In the proposed project we study ‘Lens Epithelium Derived Growth Factor/p75’ (LEDGF/p75), originally discovered in our research group in 2003 as a cellular cofactor of the human immunodeficiency virus type 1 (HIV-1), the causative agent of the acquired immunodeficiency syndrome (AIDS). Subsequent research revealed that LEDGF/p75 has a similar role in MLL mediated acute leukemia. In both cases LEDGF/p75 tethers a protein(-DNA) complex to the chromatin. We could show that disruption of this chromosomal localization was sufficient to block HIV replication as well as to hold back the development of MLL mediated acute leukemia. These results feed our hypothesis that LEDGF/p75 is a chromatin tethering hub and a valid target for several diseases. LEDGF/p75 is also known to bind Jpo2, a protein brought in connection with several mental disorders and the development of medullobalstoma, the most common malignant brain tumor in children. In this project we will investigate the molecular mechanism of LEDGF/p75 tethering, explore the Jpo2-LEDGF/p75 interaction as a new target to treat Jpo2 mediated diseases and develop new drugs that can inhibit the MLLLEDGF/ p75 interaction.