Epigenetic consequences of MLL fusion protein expression

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Certain subtypes of particularly aggressive leukemia are characterized by the presence of a chromosomal translocation that affects the long arm of chromosome eleven. This molecular event creates fusion proteins composed of parts derived from the chromatin modifying protein MLL fused to a member of a complex that normally promotes transcriptional elongation. In combination these protein chimeras work as aberrant transcription factors. Besides increasing the production rate of target RNAs, MLL fusions are also able to neutralize repressive factors (Polycomb proteins). Thus MLL fusions inactivate a safety mechanism that would normally prevent the hyper-activation of target genes leading to cellular transformation and leukemia. In this application we propose to investigate the biochemical mechanisms and the associated factors to understand how MLL fusions counteract repression. In addition we would like to examine if the frequent deletion of a tumor suppressor gene in leukemia cooperates with epigenetic treatment to exacerbate MLL fusion induced transformation.