Inositide-modifying enzymes: a cooperative role in regulating nuclear morphology during differentiation of myeloid...

Differentiation and functional response of mature myeloid cells require cytoskeleton remodelling in a dynamic system that involves subcellular organization and regional signalling. Within the myeloid lineage, neutrophils constitute a cell type in which different cell compartments, and predominantly the nucleus, undergo distinctive large changes involving actin reorganization. In the context of the progressive elucidation of the nuclear structure and composition that has been achieved in the last two decades, it is now clear that the nucleus possesses an ordered and dynamic skeletal structure which shares many properties with the cytoskeleton, and the full set of substrates and enzymes that participate in the inositol lipid metabolism. Consolidated evidence indicate that the changes in cytoskeleton assembly are regulated also by phosphoinositides in a way dependent on their local concentration and availability. Indeed, enzymes able to affect the amount and phosphorylation of inositol lipids can play fundamental roles in determining the architectural transitions of the cell. The expression pattern and the changes of activity of PLC and PI 3-K in the nucleus during differentiation of tumoral myeloid precursors suggest that these enzymes play a crucial role in modifying the intranuclear pool of phosphoinositides, which in turn induce the changes in nucleoskeleton associated to granulocytic maturation. It can be speculated that defective control of nucleoskeleton assembly is one of the causes of dysregulated cell maturation or differentiative block in the course of myeloid leukemias. Inositide modifying enzymes can thus be regarded as potential targets for molecularly designed therapeutic intervention on hematological malignancies.