Function of the HAT activity of MOZ

The MOZ gene is involved in leukemia in three independent myeloid chromosomal translocations fusing MOZ to the partner genes CBP, P300 or TIF2. All these genes encode enzymes containing a histone acetyl transferase domain (HAT) suggesting that aberrant modification of histones or other factors could provide the first step in the route to oncogenicity.  We specifically addressed the role of the HAT activity of MOZ during haematopoiesis by generating a mouse strain that carries a single amino acid change in the HAT domain of MOZ.  Analysis of these mice has revealed a profound defect in haematopoiesis.  The numbers of haematopoietic stem cells and their potential is dramatically affected in homozygous mice.  These in vivo results were confirmed with ES cells mutated for the HAT activity of MOZ as again less haematopoietic precursors are generated with the mutated ES cells.  Altogether these results demonstrate the critical role of MOZ driven acetylation in the balance between proliferation and differentiation during haematopoiesis.  We are currently investigating the precise molecular and cellular mechanisms affected in absence of the HAT activity of MOZ.