INHIBITION OF GRANULOCYTIC DIFFERENTIATION BY MNOTCH1

Effective hematopoiesis requires the commitment of pluripotent and mul tipotent stem cells to distinct differentiation pathways, proliferatio n and maturation of cells in the various lineages, and preservation of pluripotent progenitors to provide continuous renewal of mature blood cells. While the importance of positive and negative cytokines in reg ulating proliferation and maturation of hematopoietic cells has been w ell documented, the factors and molecular processes involved in lineag e commitment and self-renewal of multipotent progenitors have not yet been defined, In other developmental systems, cellular interactions me diated by members of the Notch gene family have been shown to influenc e cell fate determination by multipotent progenitors. We previously de scribed the expression of the human Notch1 homolog, TAN-1, in immature hematopoietic precursors. We non; demonstrate that constitutive expre ssion of the activated intracellular domain of mouse Notch1 in 32D mye loid progenitors inhibits granulocytic differentiation and permits exp ansion of undifferentiated cells, findings consistent with the known f unction of Notch in other systems.