The role of MOZ in normal and leukemic hematopoiesis

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DESCRIPTION (provided by applicant) Differentiating hematopoietic progenitors demonstrate an orderly maturation of chromatin, a progression that provides distinctive morphologic cues as to a cell's identity and stage of maturity. These nuclear changes, visible under the light microscope, mirror the changes in gene expression that hematopoietic stem cells undergo as they differentiate towards the various mature hematopoietic lineages. However, it is becoming increasingly clear that changes in chromatin structure do not merely reflect the molecular decision making of transcription factors and the signaling pathways to which they respond. Rather, changes directed at chromatin remodeling help to determine global patterns of gene expression, patterns which can be inherited and enhanced with each cell cycle. Many important hematopoietic regulators have been identified due to their involvement in leukemia-associated chromosomal translocations. The MOZ gene, situated at chromosomal band 8p1l, is involved in three independent myeloid leukemia translocations. MOZ partner genes disrupted by t(8;16), t(8;22), and inv(8) are, respectively, the CREB binding protein (CBP) at 16p13, P300 at 22q13, and TIF2 (NCoA-2) at 8q13; all three partners are histone acetyltransferases and nuclear receptor coregulators. MOZ is a putative histone acetyltransferase (HAT) and the founding member of the MYST family of HATs, a family that includes proteins involved in cell cycle regulation, chromatin remodeling, and dosage compensation. MOZ's structure suggests that, like CBP/P300 and other members of the HAT superfamily, MOZ participates in protein complexes that modulate both transcriptional activity and chromatin structure. This proposal tests the hypothesis that MOZ is a histone acetyltransferase and transcriptional coregulator that plays an important role during hematopoiesis. Disruption of the MOZ gene by chromosomal translocations is proposed to interfere with critical hematopoietic signaling pathways, disrupt myelopoiesis, and contribute to the development of acute myeloid leukemia. The specific aims of this proposal are to 1) characterize MOZ expression during embryonic development, hematopoiesis, and the cell cycle using northern blotting, western blotting, in situ hybridization, and immunohistochemistry; 2) assess MOZ's coregulatory functions, and its dependence on an intact acetyltransferase activity, using transient and retroviral-mediated stable transfection assays and microinjection studies in hematopoietic and non-hematopoietic cells; and 3) define how disruption of the normal functions of MOZ affects murine embryonic development and hematopoiesis using targeted disruption of the MOZ gene. The long term goal of this project is to understand how MOZ contributes to commitment and terminal differentiation during hematopoiesis.